Jan

Introduction:

The spectrum of psychiatric illness in Systemic lupus erthyromatosus (SLE) include psychotic, depressive, subtle cognitive and personality disorders of histrionic type. The occurrence of psychiatric manifestations in SLE varies widely from 5 to 83%. It is postulated that there is a direct action of the disease on the central nervous system by autoantibodies namely anti phospholipid and anti-ribosome P auto antibodies or cytokines like interleukin 2, interleukin 6, alpha interferon ¹. During the course of the disease side-effects of glucocorticosteroids and hydroxychloroquine or anxious reaction to chronic and potentially lethal illness is postulated to be another mechanism of psychiatric manifestation of SLE . SLE patients are prone to develop myriad of psychological distress in addition to neuropsychitric manifestations which require a social and psychological support. While some of these manifestations are treated by corticosteroids and psychotropic drugs¹ medications with anticholinergic side-effects, like phenothiazines, tricyclic antidepressants and hydroxyzine which enhance the oral dryness should be avoided in SLE.

Clinical scenario:

A 27-year-old male suddenly developed aggressive behaviour for the first time in his life ,while on his work place. The patient had no insight into his illness and was brought to the local psychiatric hospital by his colleagues where he was admitted as a case of acute mania. He was managed with electroconvulsive therapy (EST) in addition to antipsychotic medication as neuro imaging including CT scan and MRI brain were normal. A few days later , the patient was discharged on anti-psychiatric medicines. However, after six months while on antipsychotic medication, he developed a low grade fever .He was admitted to a local hospital where in addition to base line investigations a lymph node biopsy was done which revealed follicular hyperplasia, without any abnormal cell. Patient’s HBV, HCV, HIV were negative. The patient developed anorexia , significant weight loss and progressive difficulty in getting up from a sitting position .He also developed shortness of breath and presented to King Abdul Aziz specialist hospital in Taif, Saudi Arabia virtually in a bed bound state . He was admitted in the intensive care unit of the hospital .The examination revealed pallor, generalised lymph-adenopathy, palmer rash, alopecia and mouth ulcers. The patient had mild pericardial effusion and Mitral regurgitation (MR)++ on echocardiography. Further evaluation showed significant proteinuria. Serum ANA, dsDNA were positive .Lupus anticoagulant was negative. Keeping in view above symptoms and signs the patient was diagnosed as a case of SLE² (Mouth ulcers, Pericardial effusion ,ANA positive , dsDNA positive ) The patient was managed with pulse dose of methylprednisolone 1g intravenously (IV) daily for 5days, followed by oral prednisone 60 mg once daily, which was tapered on follow up . Patient tolerated the treatment well and improved progressively . He became ambulatory and rejoined his job. The psychiatric medications were stopped.

However, on follow up the patient continued to have proteinuria 1.8 gm/24 hr. He was readmitted and the kidney biopsy revealed class IV lupus nephritis. He was given pulse cyclophosphamide 1gm/m² intravenously and later started on tablet Mycophenolate 1.5gm once daily. The proteinuria improved and he is following our clinic for the last two years now .Patient’s follow up investigations are shown in table 1.

Table: 1 Patients’ hospital investigations and results

Discussion:

The correct diagnosis of central or even peripheral nervous system manifestations in patients with SLE can be challenging because of many SLE-related and non-SLE-related processes present in a patient. The index case proved to have acute mania as the first manifestation of SLE which remained under oblivion till he developed serositis another complication of SLE. While this patient came to clinical attention after one year a case of SLE masquerading schizophrenia for 14 years was reported by Funaunchi et al³. In another report, a 14-year-old boy with a two-year history of cognitive dysfunction and behavioural problems SLE was diagnosed after two years⁴ . It appears that the psychiatric symptoms may occur as the first manifestation of juvenile SLE. It will not be out of place to mention that the psychiatric manifestation can be at times dire which could even result in harm to others in a given society. The case of Folie a trios syndrome, characterized by the transfer of delusional ideas from one person to two other persons culminating in murder has been reported in a patient with SLE⁵ . In a significant retrospective data from China (a cohort of 518) neuropsychiatric manifestations in SLE were observed in 96(19%) of the above study cohort . The seizure disorder accounted for the most prevalent disorder of neuropsychiatric manifestations (NP) of SLE followed by cerebrovascular disease and acute confusional states. In the above study, 96 patients with psychiatric symptoms, acute psychosis was observed in 10(11%)patients. Authors in this study were of the opinion that this percentage could have been higher if subtle cognitive dysfunction were included as well. Authors of the same study further concluded that the antiphospholipid antibodies were significantly associated with NP manifestations, especially cerebrovascular disorders⁶.

The autoantibodies have been found to be biomarkers for future neuropsychiatric events in SLE. A prospective study throughout ten years conducted among 1047 SLE patients demonstrated that individuals who had evidence of lupus anticoagulant (LA) were at an increased future risk of intracranial thrombosis. Further, those with anti-ribosomal P antibodies were at an increased future risk of lupus psychosis⁷. The Lupus anticoagulant in the index case was negative, and anti-ribosomal P antibodies were not available . A study by Sanna et al⁸ have shown that an association exists between anti-NR2 antibodies and depressed mood in addition to decreased short-time memory and learning. Authors in this study concluded that antibodies to NMDA receptors thus might represent as one of the several mechanisms for cerebral dysfunction in patients with SLE.

The CT scan brain of the index case was normal. However, massive bilateral calcification of sub-cortical structures in a patient with SLE with the psychotic disorder has been reported^9. The psychiatric diseases are related to vasculitis and non-inflammatory vasculopathy of the small cerebral blood vessels. Further, a study has shown that ninety per cent of the patients with psychosis, organic brain syndrome or generalised seizures had increased IgG antineuronal activity as compared with only 25 per cent of the patients who presented with hemiparesis or with chorea/hemiballismus. The authors in the above study concluded that the diffuse central nervous system manifestations of SLE are a direct result of the interaction of the antibody with neuronal cell membranes¹⁰.

The management neuropsychiatric manifestation in SLE should include treatment of the disease itself and specific psychotropic treatment. The index case had rapid improvement following Glucocorticosteroid therapy. Intravenous infusions of immunosuppressive agents, such as cyclophosphamide, have been found to be effective in such conditions ¹ . Psychotropic drugs may be used, but it is prudent to mention that SLE-inducing drugs, like chlorpromazine, carbamazepine and lithium carbonate must be avoided. Following treatment with steroids, the index case improved and all his antipsychiatric medications were finally stopped and he resumed his job.

To conclude the index case highlights that even though SLE is more frequent among females of childbearing age but males are no way immune to SLE . While evaluating patients with multiple unexplained somatic complaints and psychiatric symptoms SLE ought to be ruled out. The existence of neuropsychiatric manifestations in SLE constitutes an indisputable clinical reality that every practitioner must be able to recognise and treat.

Background

Stress-Induced Cardiomyopathy (SCM), also known as Takotsubo Cardiomyopathy or Apical Balooning Syndrome, is an acute, transient and non-ischaemic cause of left ventricular dysfunction often precipitated by periods of stress¹. Diagnosis often follows evidence of left ventricular hypokinesia despite a normal coronary angiography. Prevalence is often underestimated, with an estimated 7% of suspected myocardial infarctions being in fact SCM². We report a unique case of multi-nodal dysfunction following SCM.

Case Report

A 73-year old lady presented to our emergency department following a sudden onset of central, non-radiating chest heaviness 8 hours prior. She was a known chronic smoker of 20 pack years, and hypertension which had been left untreated for over 10 years. An initial electrocardiogram (ECG) revealed sinus bradycardia and T-wave inversions in the inferior, septal and lateral leads (Figure 1). Her Troponin-I levels was raised at 6532 pg/ml. She was treated as a Non-ST elevation myocardial infarction and was admitted to the coronary care unit for closer monitoring. She was kept on telemetry overnight, which disclosed several episodes of bradycardia. Rhythm strip revealed various transient conduction defects, including that of sinus node dysfunction (SND) and atrioventricular node (AVN) dissociation, although she remained asymptomatic throughout (Figure 2).

Figure 1: Electrocardiogram revealing sinus bradycardia, with T-wave inversion in the inferior, septal and lateral leads.

Figure 2: Telemetry rhythm strip revealing transient episodes of (a) sinus node dysfunction (SND) and (b) atrioventricular node (AVN) dissociation.

Figure 3: Electrocardiogram revealed ST-segment elevation with associated T-wave inversions in the inferior, septal and lateral leads.

Figure 4: An ‘Apical 4-Chamber’ view on echocardiography, revealing an akinetic apex on (a) diastole and (b) systole.

Unfortunately, following an episode of chest pain the following morning, her troponin levels and an electrocardiogram were repeated, showing a rise of the former to 12 996 pg/ml. A repeat ECG revealed evidence of ST-segment elevation in previously affected leads (Figure 3). She was brought into the catheterization laboratory within 1 hour. Her coronary angiogram showed no evidence of coronary obstruction. An echocardiogram was performed, which revealed an akinetic apex (Figure 4).

Upon further history taking, it was revealed that she was recently made redundant from her job as a cleaner, several hours prior to her presentation to the emergency department. Prior to that, she denied any other emotional or physical stressors. She was diagnosed as having Stress-Induced Cardiomyopathy (SCM). Following an observational period of close to 48 hours, she was allowed home. A 48-hour Holter monitoring was performed approximately 3 weeks from her initial admission, which returned unremarkable. A repeat echocardiography was also performed, revealing normal wall motion abnormality which further support a transient SCM.

Discussion

Despite being transient, multiple complications can arise from the condition, including arrhythmias. Prevalence of arrhythmias varies greatly, depending on population and types of defect (15% suffering atrial fibrillation, 2-5% of tachyarrhythmias, 2-5% of bradyarrhythmias and 5% of AVN dissociation amongst others)^3,4. This is largely due to evidence being based on retrospective case report and series, leading to severe underestimation of their true prevalence. We suspect cases of sinus node dysfunction are far more uncommon, with only a handful of case report of note, and one retrospective review of 816 patients quoting a rate of 1.3%⁵. There are no reports of concomitant sinus node and atrio-ventricular node dysfunction, to our knowledge.

Proposed mechanisms for SCM-induced nodal dysfunction include reduced coronary flow to conduction tissues due to left ventricular dyskinesia, cathecolamine-driven coronary and microvascular vasospasm leading to both reduced blood supply and direct cardio-toxicity effects, and continual ischaemia-driven fibrosis of nodal tissue⁶. However, there have been reports of SND-triggered SCM, likely secondary to adrenergic compensative activation following bradycardia events. In both scenarios, pre-existing, subclinical SND may lower the threshold of developing significant, symptomatic bradycardia^7-10. This is important to note, as majority of patients affected by SCM are post-menopausal women whom are already at risk of age-related SND.

In our patient, the SCM may have likely induced both SND and AVN dissociation, as subsequent 48 hours Holter monitoring, 3 weeks from presentation, was unremarkable. Furthermore, the patient denies any previous syncopal or pre-syncopal symptoms. However, the possibility of subclinical SND could still have existed, as we had earlier discussed, and ideally an internal loop recorder for prolonged monitoring, catheter-based electrophysiology studies and a Cardiac Magnetic Resonance Imaging to detect nodal and conduction tissue fibrosis would assist in ruling out pre-existing nodal dysfunction. However, due to financial and pragmatic reasons (as patient was asymptomatic), the patient declined further investigations, opting for periodic clinic reviews instead.

Conclusion

Both nodal and conduction tissue blocks are a rare but significant complications that can occur following SCM. The occurrence of SND following SCM should lead clinicians to routinely investigate for pre-existing conduction tissue diseases, if not already performed and allows for earlier device implantation if deemed indicated.

Introduction

The Royal College of Psychiatrists (RCPsych) launched its five-year Recruitment Strategy in 2011 aiming to achieve a 50% improvement in recruitment to core psychiatry training and a 95% fill rate of posts by the end of the five-year campaign ⁽¹⁾. The primary focus of this campaign was on recruiting UK medical graduates.

Two of the Strategy’s main aims were to highlight good practice in undergraduate teaching and to improve the teaching skills of psychiatrists to inspire and influence medical students during their psychiatry curriculum.

The Strategy stressed the importance of good clinical placements in psychiatry and recommended that medical students should ideally be placed only with ‘the best teachers and welcoming teams’ avoiding colleagues who are disillusioned with psychiatry or not happy with their jobs.

It is therefore essential that psychiatrists and other clinicians play an important role to improve the medical students placement in their workplace in order to give the students a positive expereince of this speciality and hopefully promote it as a future career option.

Background

Fourth-year medical students from the University of East Anglia (UEA) spend two months rotating through various mental health services as part of their clinical placement in the Mind Module (also known as Clinical Psychiatry or Module 11).

As part of this rotation, students are placed in Old Age Psychiatry for six days over a two-week period. They shadow clinicians in two community teams, two inpatient wards and the Electro-Convulsive Therapy (ECT) clinic. All of these teams are based at the Julian Hospital in Norwich.

The students are encouraged to talk to patients and carers and perform basic clinical tasks such as mental state examination and risk assessment. Table 1 summarises the learning outcomes for students during their placement.

After each rotation, each student is asked to complete a feedback form regarding their placement. This feedback helps the module leads and clinicians to improve the students learning experience.

Before the implementation of our placement improvement project, the students did not feel that they were meeting their learning outcomes. Table 2 summarises the major areas that needed improvement.

Student dissatisfaction with clinical placements is not unique to psychiatry. Research has shown that educators and learners face significant challenges when teaching and learning take place in any clinical setting. See Table 3 for a summary.

One of the biggest challenges of teaching in clinical settings is how to provide a welcoming and supportive learning environment in a busy and time constrained practice. We found that one of the main reasons for clinicians to be reluctant to have students shadowing them is the challenge of providing a dual role of caring and teaching simultaneously.

The placement improvement project

The improved structure of the student's’ placement in Old Age psychiatry was based on the tenet that clinical placements should provide various clinical experiences that include interaction with patients and professionals from various grades in addition to face to face teaching in small groups ⁽³⁾. The authors took over full responsibility for coordinating the students’ placements and liaising with the various supervising clinical teams. This ensured clear leadership and consistency in organising the placement.

The improved placement structure started in October 2015 with the first cohort of medical students coming to their clinical placement after the summer break. Table 4 gives a summary of the changes implemented.

The information pack sent to the students before the placement contained information about the hospital environment (location, map, parking, travel arrangements, key codes and useful contact numbers) and a detailed timetable (and email address) of the clinician supervising the student each day during the placement. Also, it included useful information about the mental state examination and the Mental Health Act, information that had been requested previously by medical students.

Sending information before the placement has been shown to be beneficial in students’ electives ⁽⁴⁾ and this is especially important in psychiatry which can be experienced as less structured than other medical specialities and where students are required to travel to various hospitals and clinics bases. As a result, students felt that they were expected and had a clearer sense of where they should be and who would be supervising or teaching them. Later student feedback reported that these changes had contributed directly to an improved learning experience.

The timetable design ensured that every student would have the chance to experience working in several settings in Old Age Psychiatry, including community, inpatients, ECT and the Memory Clinic. It was also noted that a two-week placement in any psychiatric team could not easily give a student a sense of patient ‘recovery’. It was, therefore, decided that students see a patient who had been discharged from the ward, e.g. with the care coordinator.

The rota of the ‘Meet and Greet’ event on the first day of the placement ensured that the workload is spread among the clinicians and helped sustain the necessary levels of enthusiasm and energy. Previously, this task had repeatedly fallen to just a few clinicians.

The participation of all professionals in the clinical team in supervision and teaching helped the students to better understand the different roles of clinicians within the multidisciplinary team and enriched their learning experience. To achieve this, we attempted to allocate sessions with a clinical psychologist, care coordinators, memory assessment nurses and members of the intensive support team. It also had the bonus of ensuring that the workload of teaching was spread more equally among clinicians.

Attendance at ward rounds and community MDT meetings could be a valuable experience but only if the process is explained, and – in the ward round – the student is briefed on the clinical history and background of the patients. For these reasons, supervising clinicians were reminded to give this information to the students attending such meetings.

The weekly teaching sessions provided an opportunity for the students to present case histories of patients they had seen and to discuss their management. Clinicians could also give a formal didactic teaching on a specific topic, for example, mental state assessment or risk assessment in psychiatry.

The letters of thanks to the participating clinicians served as an added benefit (in addition to the satisfaction of teaching others) to sustain their motivation and reward them for their contribution to the teaching of medical students. The psychiatric trainees used the letter to demonstrate their skills in teaching in their portfolio.

Benefits of the new placement structure

Helping students to feel supported before, during and even after their placements was a high priority in this project. Research has shown that learners rank the need for support and guidance in workplace environments as high and it is an essential requirement for a successful learning experience ⁽⁵⁾. This extra support is particularly crucial in psychiatry which is perceived by many students to be difficult and challenging ⁽⁶⁾.

The support provided to the students in the improved structure was in the form of having the contact details of the rota coordinators, their supervising clinicians, the administration team (medical secretaries, site manager for parking permits) and some other useful numbers for various locations and clinics.

While improving the organisation of the placement, changes were aimed to reduce the commitment of teaching and supervision for clinicians and spread it more equally among the members of the team.

Students reported that they found home visits during the placement the most useful part of their placement and the most interesting. This is an invaluable experience with the student having a significant amount of time in a one to one interaction with a clinician (including during the travel from one location to another) and then observing the clinician ‘in action’ with patients at home. This experience highlights the role of ‘professional socialisation’ ⁽⁷⁾ that is considered by educators as a significant process in the development of a sense of a shared professional identity and responsibility in both the clinician and the learner.

Furthermore, using non-medical professionals to supervise and teach students has been valued by students ⁽⁸⁾. It enriched the clinical placement with the concept of (Inter-Professional Learning) which is an active learning from and with professionals from other disciplines allied to medicine. This style of education has been shown to improve students’ communication with professionals from different disciplines and to have a better understanding of the nature of the multidisciplinary teamwork and the roles of each member of the team ⁽⁹⁾.

While improving the organisation of the placement, changes were aimed to reduce the commitment of teaching and supervision for clinicians and spread it more equally among the members of the team.

Balint groups and improving student placements in psychiatry

Balint groups were pioneered by the Hungarian psychoanalyst Michael Balint who introduced this model in the late 1950s after running seminars for general practitioners in the UK with his wife, Enid. ⁽¹⁰⁾

Balint recognised the intense emotions that affect the doctor and the patient and encouraged clinicians to talk about these feelings in groups, which later came to be known as Balint groups.

Research has shown that Balint groups for medical students can increase the students’ empathy towards patients with chronic mental illness and improve their ability to cope with complex clinical situations ⁽¹¹⁾. It also helps them to engage in reflection about their professional growth and to develop their identity as future doctors ⁽¹²⁾. Most importantly, this psychotherapeutic approach it allows them to reach a deeper understanding of the emotional impact of their patients ⁽¹³⁾. It was felt that the students would benefit from this model to help with the various emotions evoked by dealing with patients they would encounter in Old Age Psychiatry, in particular, dementia.

The student feedback was very positive for the Balint group. One student commented. It is inevitable to have experiences with patients that leave you with a feeling, whether that be positive or negative. To be able to look back at those times, talk them through, be listened to and have others reflect things back that you may not necessarily have realised yourself, is invaluable’.

Patient and carer involvement in clinical education

Clinical education in the workplace has always depended on patients and carers in its design and delivery. Students value seeing patients and learning from their experiences. However, the evidence suggests that patients are not routinely involved in the design of the curriculum or clinical placements despite calls to actively engage them in teaching and training ⁽¹⁴⁾.

Students were given the opportunity to learn from patients and carers through regular and supervised contact with them. They also attended a workshop on dementia and viewed a DVD showing the experiences of a woman with dementia and depicting how the world might be seen from her perspective. Feedback from students was very positive for these opportunities.

Medical students placement and Electro-Convulsive Therapy (ECT)

Students are allocated to spend one day in ECT clinic during their two-week placement in Old Age Psychiatry. Research has shown that many medical students have negative attitudes and unjustified reservations about ECT and its therapeutic applications ⁽¹⁵⁾. However, these views can change with education about this therapy during clinical placements and encouragement of the students to talk to patients and read about its indications and effectiveness in people with severe mental illness ⁽¹⁶⁾. Seeing the procedure first hand would, therefore, help the student gain confidence to challenge the stigma attached to ECT and to explain this treatment to their future patients.

Feedback from the students following the implementation of the placement improvement project

The feedback from medical students and clinicians was very positive. The students enjoyed their placements and felt that they gained useful knowledge and skills. Above all, they felt welcomed in the clinical settings and settled very nicely into the teams.

Figures 1 and two summarise some comments from the medical students following the placement. This feedback was collected by Norwich Medical School as part of the regular monitoring of clinical placement for medical students.

Figures 1 and 2: Feedback from students after the implementation of the changes to the clinical placement:

Limitations

There were some challenges in the implementation of this improved model. First is not always easy to recruit non-medical members of the clinical teams to take students. There are some reasons for this including lack of confidence or experience in teaching, a belief that it is “not their role”, or concern about the increasing demands on their time. Others already had students in their discipline. This was addressed by briefing the professionals about what the students need to achieve at the end of the placement and encouraging them to be involved in the supervision. The introduction of nursing revalidation in April 2016 may help more nurses to get involved. ⁽¹⁷⁾

Conclusions and recommendations

This paper describes a clinical placement improvement project for medical students in Old Age Psychiatry. The changes focused on the enhancement of organisation, supervision and teaching.

Our improvement project is ongoing, and there are areas needing further improvement, for example, more active involvement of patients and carers in the teaching and learning of medical students is necessary. It is planned to achieve this by inviting patients and carers to tell their personal stories to the students in a small group.

Organisers of students’ placement in secondary or primary care need a systematic approach to filling allocation slots to ensure that all students receive a similar and broad exposure to their speciality. It can be dispiriting and stressful to ask for volunteers constantly. They need to have good relationships with their clinical colleagues of all disciplines, and to be willing and assertive enough to go around and ask colleagues in person rather than sending email requests.

Psychiatric educators have a significant role to play in the improvement of clinical placements for students as this will hopefully contribute to improving recruitment to this medical speciality that is undergoing a recruitment crisis. Research has shown that there is a positive correlation between the length and quality of clinical placement and the likelihood of choosing psychiatry as a future career. ⁽¹⁸⁾

Teaching Points

• Despite advances in the management of ectopic pregnancies an emphasis must be given on improving the understanding of the women and the healthcare professionals of the pathophysiology of haemorrhagic shock.
• Educating the public and all health care professionals about the phrase “Think Ectopic” as a main differential in any women of childbearing age with atypical signs and symptoms of general ill health is paramount.

Précis

The significance of effective communication within multidisciplinary teams especially in emergency situations towards optimising patient care and saving lives cannot be understated.

Case Report

A 27-year-old woman who claimed to be unaware of her current pregnancy collapsed at her home. She was not known to have any co-morbidities. Paramedics were called and found her to be in cardiac arrest with pulseless electrical activity. Cardiopulmonary resuscitation (CPR) was immediately commenced. Spontaneous circulation returned after 13 minutes of CPR at home.

She was then transferred to the emergency department. On arrival to the emergency department her Glasgow Coma Scale (GCS) was 3. She had a pulse rate of 130 beats per minute; unrecordable blood pressure; haemoglobin of 55g/l; metabolic acidosis with a pH of 6.8; lactate > 15; and a potassium of 6.6 mmol/l. She was resuscitated and gradually regained consciousness with a GCS of 15.

In the midst of stabilising her condition and unaware of her pregnancy, a urine pregnancy test was obtained following siting of a urinary catheter. A positive pregnancy test prompted notification to the gynaecology team who performed ultrasonography imaging which revealed significant haemoperitoneum. An immediate decision was made to perform laparotomy in view of the most likely diagnosis of a ruptured ectopic pregnancy.

Laparotomy revealed a 3.5 litre of haemoperitoneum secondary to a ruptured right sided tubal ectopic pregnancy. A right salpingectomy was performed. The patient was subsequently transferred to the intensive care unit as her serology results were consistent with multi organ failure with a platelet count of 46 (10⁹/L); creatinine of 194 mmol/L; estimated glomerular filtration rate (egfr) of 27 mls/min/ 1.73 m²; alanine transaminase (ALT) of 441 IU/L; and alkaline phosphatase (ALP) of 49 IU/L.

She made an uneventful recovery as demonstrated in figure 1 by the improving serological parameters and was discharged home after 6 days.

Figure 1: The cumulative serology- full blood count, liver function tests, urea and electrolytes, clotting profile.ankle

Discussion

The confidential enquiry report into maternal deaths – UK has shown a decreasing trend in the case fatality rate in women with ectopic pregnancies. This has been suggested to reflect earlier detection and immediate treatment of ectopic pregnancies. However unforeseen tubal rupture with major haemorrhage continues to be a source of major morbidity and mortality. Ectopic pregnancies account for 3-4% of pregnancy related deaths. ⁴

The classical triad of symptoms encountered in ectopic pregnancy includes pain, vaginal bleeding and amenorrhoea. ¹ Worryingly, as illustrated by our case, rarely these women may present in a state of collapse even before the diagnosis of pregnancy is made. ⁴

Pathophysiology of multi-organ failure following haemorrhagic shock

Our case clearly demonstrates the detrimental multi-systemic effects and subsequent threat to life created by haemorrhage from a ruptured ectopic pregnancy. Acute haemorrhage results in decreased cardiac output and pulse pressure that is detected by baroreceptors in the aortic arch and atrium. Neural reflexes subsequently cause an increased sympathetic outflow to the heart and other vital organs resulting in vasoconstriction, and redistribution of blood flow away from non-vital organs. Neuroendocrine responses activated by neural reflexes play a major role in homeostasis during haemorrhage. Elevated aldosterone and cortisol secondary to raised adrenocorticotrophic hormone secreted by the pituitary gland leads to increased water absorption in the kidneys. The reduced tissue perfusion to non-vital organs results in insufficient delivery of oxygen and nutrients required for cellular function. ²

The resultant hypoxia leads to anaerobic metabolism and hence lactate production and metabolic acidosis. Hyperlactaemia is defined when serum lactate is greater than 4 mmol/l. ³ A level of 15mmol/l as demonstrated by our case highlights the extent of shock the patient was in.

Endogenous heat production is restricted by anaerobic metabolism, which in turns exacerbates hypothermia that is likely to be predisposed by the administration of intravenous fluids and blood products. Hypothermia is one of the reversible causes of pulseless electrical activity and a core temperature of less than 35°C is itself an independent predictor of mortality after major haemorrhage.

Furthermore, our case revealed a severe acidosis with a pH of 6.8, which is reflective of widespread cellular anaerobic respiration secondary to hypoxia as a result of inadequate perfusion. Widespread literature has shown that a pH of less than 7.2 is associated with decreased contractility, low cardiac output, bradycardia, arrhythmias and decreased blood flow to the liver and kidneys. This can lead to multi-organ failure.⁶

Many patients with severe haemorrhage can establish coagulopathy very quickly as our case has demonstrated. At present there is nouniversally established definition of coagulopathy though many experts use prolonged prothrombin time as an indicator of coagulopathy. Our case presented with a prolonged prothrombin time of 14.8 seconds. The pathophysiology is complex and stems from immediate activation of multiple haemostatic pathways including fibrinolysis, platelet and endothelium dysfunction. Furthermore, acute phase response after resuscitation measures can create a prothrombotic state. Sometimes, disseminated intravascular coagulation can occur in those who are insufficiently resuscitated or not resuscitated in a timely manner. ⁷

Effective multi-disciplinary input

This case clearly highlights that the responsibility does not solely rely on the surgeon who is required to cease the bleeding but also on the multi-disciplinary specialists including paramedics, emergency clinicians, nursing staff, anaesthetists and haematologists. This is a vital component of resuscitation management during emergency situations.

Appropriate initial fluid management

The management with intravenous fluid resuscitation remains challenging as some evidence suggests that aggressive fluid resuscitation can be detrimental because it can lead to dislodging of clots and dilutional coagulopathy leading to increased risk of haemorrhage. ⁵

Clinicians supporting this hypothesis suggest to cautiously administer fluid resuscitation with the aim of maintaining a subnormal blood pressure (systolic of 70-90 mmHg), whilst allowing sufficient oxygen delivery. The very early use of crystalloids and blood products is paramount to help treat acute coagulopathy. ⁷

Immediate surgical treatment

Recourse to immediate surgical cessation of bleeding is a vital part of the resuscitation process, and must not be delayed. ⁷ The presence of free fluid in the abdomen and a positive pregnancy test immediately alerted an ectopic pregnancy as the most likely diagnosis. The majority of women of reproductive age are free of comorbidities with a greater ability to adapt to resuscitative measures and hence showing quicker recovery.

Conclusion

Despite advances in the management of ectopic pregnancies an emphasis must be given on improving the understanding of the women and the healthcare professionals of the pathophysiology of haemorrhagic shock. Educating the public and all health care professionals about the phrase “Think Ectopic” as a main differential in any women of childbearing age with atypical signs and symptoms of general ill health is paramount.

Furthermore, the significance of effective communication within multidisciplinary teams towards optimising patient care and saving lives cannot be understated.

A 70-year-old man presented in the winter with a four-week history of redness of the left anterolateral leg. He first noticed a slight “tenderness” in the area when showering; the discomfort lasted only a few days. Over the next week, he noticed redness developing. It is now painless and not pruritic, warm, or peeling. He has not applied any topical lotions or creams. He has not had an exposure to new soaps or detergents. He feels well, without fever or weight loss. He has a diagnosis of hypertension and lumbar radiculopathy with an L5 discectomy and resultant leg numbness. He is retired and does not smoke or drink alcohol; his hobby is woodworking in his garage.

Physical examination reveals normal vital signs. On his left anterolateral leg, he has an 8 cm, irregular patch of reticulated erythema with both hyperpigmentation and scaling. The lesion is non-palpable. He has decreased sensation in an L5 distribution on that leg, which was unchanged from prior examinations. These skin findings are shown in Figure 1.

Figure 1

Question: Based on history and physical examination, which of the following is the most likely diagnosis?

• Livedo reticularis
• Erythema ab igne
• Livedo racemosa
• First-degree burn

Discussion

The answer is erythema ab igne (EAI; literally “redness from fire,”) which results from chronic exposure to moderate-intensity heat. EAI presents as a reticulated erythematous patch over the area of exposed skin. Possible secondary changes include epidermal atrophy and scaling.^1,2 With repeated exposure, brown hyperpigmentation may develop.¹ Most patients are asymptomatic, although some note a mild burning sensation. A history of repeated exposure to heat is key to the diagnosis. While cases were historically noted on skin exposed to fire, such as the arms of bakers and coal shovellers, EAI can result from our many, modern heat-sources, such as laptop computers, car seat heaters, heating pads, and, in this case, the portable space heater under the patient’s woodworking bench.^2-4 With removal of the heat source, hyperpigmentation typically regresses but may take years.^1,3 The diagnosis is clinical. A biopsy is not required to make the diagnosis, but is indicated if malignant transformation is suspected. EAI can increase risk of squamous cell carcinoma, Merkel cell carcinoma, and cutaneous marginal zone lymphoma.^1,5 Treatment is typically not necessary; topical steroids or retinoids and laser have had variable success.^1,3,4 If pre-malignant changes are detected, topical 5-flourouracil is recommended.^1,4

See Table 1 for a summary of the key characteristics and distinguishing features of each diagnosis in this selected differential.

Table 1. Selected Differential Diagnosis of Reticulated Skin Lesions in Adults

Livedo reticularis is typically more violaceous in appearance, with net-like, mottled discolouration of the skin due to deoxygenation and dilation of the venous plexus. Primary, physiologic livedo reticularis is often brought on by cold and alleviated by warming. It usually involves a larger area, such as the bilateral thighs, rather than a confined area of skin.^1,2

Livedo racemosa is a persistent variant of livedo reticularis with a characteristic, large, broken, branching pattern, often on the trunk and proximal limbs. It is generally secondary to a systemic disease, such as antiphospholipid antibody syndrome or Sneddon syndrome.⁶

First-degree burns are erythematous, dry, and painful. Instead of a reticulated pattern, as shown here, the erythema of first degree burns covers the entire area of skin that contacted the high-intensity heat source.

Introduction

The skeletal type of muscles are rarely affected by tuberculosis (TB) because they are not a preferred site for the survival and multiplication of Mycobacterium tuberculosis.¹ Even in patients with widespread involvement of the disease, TB rarely involves muscles. Petter et al recorded only one case of primary skeletal muscles TB in over 8,000 cases of all types of TB, with an incidence of 0.015%.² Few cases of tubercular myositis have been described in literature until now, mostly in adults. This, together with the decline in TB in general, makes it unlikely that one would immediately consider TB as the cause of a rectus sheath abscess.

There are only limited cases reports of isolated tubercular involvement of the anterior abdominal wall even though TB is rampant in developing countries, and with the rapid spread of acquired immune deficiency syndrome (AIDS) it has made inroads into the developed nations as well.³ We are presenting a case of primary tuberculous abdominal wall abscess, with no evidence of pulmonary, skeletal or gastrointestinal TB in an immunocompetent patient. This case report should serve as a reminder that TB, in all of its various manifestations, remains very much among us.

Case report

A 20-year-old female presented to the outpatient department of surgery, with a complaint of a progressive swelling in the left lower abdomen for the last three months. There was no history of preceding trauma, fever, cough, malaise or pain. There was no history of contact with any case of TB. On examination, there was a swelling in the left iliac fossa, measuring 8x8cm in size, non-tender with smooth and ill-defined margins, and normal overlying skin. The swelling was firm in consistency and moved with respiration. Examination of the cardiovascular and respiratory systems were within normal limits.

Laboratory investigation revealed: haemoglobin 11.5 g/dl; total leukocyte count 8510/cumm with a differential count of 54% neutrophils, 42% lymphocytes and 4% eosinophils; erythrocyte sedimentation ratio 70 mm; and enzyme-linked immunosorbent assay (ELISA) for human immunodeficiency virus (HIV) negative. The chest radiograph was unremarkable. Other biochemical blood investigations, including liver and kidney function tests, were within normal limits. Ultrasonography of the abdomen revealed a 6.5x8.5cm left iliac fossa cystic mass with a liquefied necrotic centre in the anterior abdominal wall (Fig. 1). Computerized Tomography (CT) scan of the abdomen showed an abscess in the left antero-lateral portion of the abdominal wall limited to the muscle layer (Fig. 2). Ultrasound-guided fine-needle aspiration and cytological examination revealed caseating granuloma with central necrosis, lymphocytes, and giant cells, consistent with TB (Fig. 3). The patient was diagnosed to have tuberculous abscess of the anterior abdominal wall and antituberculous treatment was started following internal medicine consultation. She improved rapidly over the next few days. After four weeks of antituberculous treatment, she responded well to the treatment and the abscess regressed considerably. The patient did not require any surgical intervention.

Figure 1. Ultrasonography of the abdomen revealed a left iliac fossa cystic mass.

Figure 2. Focal cystic collection seen in the anterior abdominal wall of the left iliac fossa with mild peripheral enhancement (white arrow)

Figure 3. Photomicrograph revealed caseating granuloma with central necrosis, lymphocytes, and giant cells, consistent with tuberculosis.

Discussion

TB of the anterior abdominal wall is a rare entity and only isolated cases are reported in the literature. Possible explanation for the rarity of muscle involvement in TB includes high lactic acid content, lack of reticulo-endothelial tissue in muscle, lack of lymphatic tissue, the abundant blood supply, and the highly-differentiated state of muscle tissue.⁴ Although none of them seems to be an adequate explanation, all theories (except the first one) have been criticized.²

Two forms of skeletal muscle involvement are recognized.⁵ In the first type the tuberculous process spreads into the muscle through direct extension from a neighbouring structure e.g. bone, joint, tendon, or lymph node. In the second type the spread is haematogenous. Our patient is of interest because she seems to have a primary tubercular anterior abdominal muscular lesion with no evidence of immunoincompetence.

A tuberculous focus in the muscle usually manifests as progressive swelling and pain. The infection is usually restricted to one muscle.⁶ There may be a frank tuberculous abscess (as seen in our case) or a nodular sclerosis followed by calcification. Ultrasonography usually shows a cystic mass of mixed echogenicity with irregular walls and a liquefied, necrotic centre. Computed scan of the abdomen usually shows a well-defined abscess in the abdominal wall.^{7, 8} Ultrasonography or CT-guided aspiration followed by cytological examination usually reveals tuberculous granulomas with areas of caseous necrosis.

Management of this entity is mainly in the form of antituberculous drugs. Surgical intervention in the form of sonography, CT-guided aspiration or open drainage is usually reserved to patients where medical treatment has failed.³ Our patient responded well to medical treatment.

Although localized swelling in the rectus abdominis muscle is commonly due to necrotizing fasciitis, rectus sheath haematoma or tumours (benign / desmoid / malignant), a rare possibility of TB should also be considered. The prognosis is good in tuberculous myositis with appropriate chemotherapy.

Conclusion

This case alerts clinicians and radiologists of the possibility of TB when considering the differential diagnosis of any lesion even in any unlikely anatomical area, especially in those regions where TB is endemic.

Overview

The term ‘designer drug’, coined in the 1980s, generally referred to various synthetic opioids based mostly on the fentanyl molecule (α-methylfentanyl) and MDMA (methylenedioxymethamphetamine) commonly known as ecstasy. Fentanyl is an extremely potent analgesic, some 100 times more potent than morphine. MDMA and fentanyl compounds were the most popular synthetic drugs initially. The terminology is confusing because although the description ‘designer drug’ seems to imply the creation of new drugs, many are not new. For example, cathinone derivatives have been reported since the late 1920s. MDMA was first synthesised in 1912, methcathinone in 1928, and mephedrone in 1929. Cathinone is chemically similar to ephedrine, cathine, methcathinone and other amphetamines.

Legal highs generally comprise cathinone stimulants and synthetic cannabinoids. Hallucinogenic agents such as salvia divinorum are also included, the latter sometimes described as herbal ecstasy. Synthetic amphetamines are not regarded as hallucinogenic, though hallucinations are experienced by some users.

Thus, the term ‘designer drugs‘ covers an array of substances which are used recreationally, are not controlled under the Misuse of Drugs Act (1971), are not licensed for ‘legal’ use, and are not regulated under the Medicines Act (1968). They are chemicals produced by tweaking or altering the molecular structure of previous well-known psychoactive agents. By stating they are ‘not for human consumption’, or are just ‘bath salts’, they can be sold legally. Hundreds of such substances are now available, reflecting the ease at which chemists can produce them.

Availability and Consumption

The World Drug Report (available on the Internet) produced annually by the UN Office on Drugs and Crime (UNODC), provides information on the worldwide manufacture and marketing of illegal drugs. The 2013 report highlights a striking rise in the availability of new substances. Part of the challenge lies in their variety - some are derived from plants, for instance, the mint plant Salvia divinorum, native to Mexico, with synthetic cathinones and cannabinoids also being major contributors in other countries.

Ease of synthesis, low cost, and resourceful marketing have contributed to the problem. Information provided via the internet, combined with minimal difficulty in the manufacture and transport from distant regions, together with lax legal enforcement, creates an ideal opportunity for legal highs to flourish. The low cost is particularly attractive though ironically legal highs probably cost more these days: for example, 1g of mephedrone costs about £16.00 more than when legislation was introduced in 2010. On the other hand MDAI (methylenedioxy-2-aminoindane), a legal stimulant and club drug which is snorted or bombed, costs about half the price of cocaine (£20 per gm). It is sometimes cheaper to buy legal highs over the internet than from a drug dealer. Part of the increase in use of legal highs may be a result of decreasing purity of other ‘buzz’ drugs such as cocaine and MDMA.As with other illegal drugs regulatory measures drive the drugs ‘underground’ and into the hands of drug dealers and the price then varies with the purity of the drug and its ease of manufacture and availability.

Some users will revert to taking an illegal drug when the legal alternative is prohibited. There is also a certain curiosity to experiment with new drugs. Even so, to keep things in perspective, consumption of more harmful familiar illegal drugs (for example, cocaine, amphetamines) has not abated, with over 315 million people worldwide thought to be using them. More worrying is that millions of individuals inject more harmful drugs such as opiates with resultant increased rates of HIV, hepatitis B and hepatitis C infection. Readers are also likely to be aware of the violence and deaths associated with drug manufacturing and supplying within countries such as Latin America.

Government Control

The Medicines Act 1968 (UK) governs the control of medicines for human and veterinary use. It defines three categories of medicines: a) prescription only medicines (POM), available solely from a pharmacist and requiring an appropriate practitioner to issue, b) pharmacy medicines (P), available only from a pharmacist, without the need for a prescription, and c) general sales list (GSL) meaning medicines bought without a prescription. The Medicines Act 1968was set up to protect patients from unscrupulous suppliers of medicines. Safeguarding the public from illegal medicines or any inaccurate and misleading labelling of medicines isparamount. However, manufacturers have managed to sell legal highs by passing them off as bath salts or research chemicals.

Phenylalkylamines analogues such as amphetamine are widely misused and because of their simple structure hundreds of amphetamine analogues have been introduced for decades. This is the reason why so many legal highs are available. Amphetamine (phenylisopropolamine), a familiar central nervous system (CNS) stimulant, has effects which last for several hours after oral intake. Methamphetamine is closely related to amphetamine and ephedrine (a mixed-acting sympathomimetic). Ephedrine and pseudoephedrine (often used for relief of nasal congestion) undergo reduction to methamphetamine, or oxidation to methcathinone. As with methamphetamines, methcathinones can be readily ‘cooked’ in the laboratory and hence the term ‘synthetic’.

Background biochemistry

Morphine, the most abundant opiate alkaloid found in the poppy plant, papaver somniferum, was first isolated in 1804. The actual term alkaloid is derived from "alkaloide" introduced in 1819 by the German chemist Carl Friedrich Wilhelm Meisner, from the Latin root ‘alkali’, and the Arabic word al-qalwī meaning "ashes of plants".

Alkaloids are a group of naturally occurring organic nitrogen-containing bases, a base being a substance with a pH above 7 which turns red litmus paper blue. They include related compounds with neutral and even weakly acidic properties and more than 3,000 different types have been identified. In addition to nitrogen, hydrogen and carbon, most alkaloids contain oxygen, sulfur, and to a lesser extent, chlorine, bromine, and phosphorus. Generally, an alkaloid contains at least one nitrogen atom in an amine-type structure, i.e. one derived from ammonia (NH₃) replacing the hydrogen atoms with hydrocarbons, for example, CH₃ or CH₂. Alkaloids generally are weak bases and some act as acid or base (amphoteric).

Alkaloids are produced primarily by flowering plants and organisms such as bacteria, fungi, and animals. Several alkaloids may be extracted from one plant.They can be purified from crude extracts by acid-base extraction and tend to have a bitter taste. Those containing a ring system are known as indole alkaloids (for example, terpenoids and steroids). Some are named after the biological species from which they are derived (morphine from the poppy plant Papaver somniferum, cocaine from erythroxolon coca, and so on). Other common examples include psilocin, caffeine, nicotine, vincristine, reserpine, atropine, quinidine, ephedrine,strychnine and quinine. Atropine is the tropane alkaloid isolated from the deadlynightshade plant Atropa belladonna, and strychnine is derived from the seeds of the Strychnos nux-vomica tree. Caffeine, cocaine, codeine (methylmorphine) and nicotine are water-soluble alkaloids. Morphine and yohimbine are highly water-soluble. Other alkaloids dissolve poorly in water yet readily in organic solvents such as chloroform or ether. The biological precursors of most alkaloids are amino acids, such as phenylalanine, tyrosine, tryptophan, histidine, and aspartic acid, among others. ¹

How are they used?

The synthetic cathinones (usually mephedrone and methylone, or M-Cats) are most commonly used intranasally (insufflated) or ingested. “Bombing” is a method of ingestion whereby mephedrone powder is wrapped in cigarette paper and swallowed. Because sniffing the drug may cause nasal burns users will often resort to ‘bombing’. “Keying” is the practice of dipping a key into powder and then insufflating, with approximately five to eight “keys” per gram. Rectal administration, gingival delivery, inhalation, intramuscular and intravenous injection have also been described. Multiple concomitant routes of administration are reported. Self-reported doses range from a few milligrams to over 1 g of powder. A typical dose of mephedrone would be 100-200mg every 1-2 hours.

Users cannot be certain of the actual contents or indeed of the purity of the drug, therefore actual dosage and exposure is highly variable. For example, when MDAI (methylenedioxy-2-aminoindane) known as Sparkle (a granular, brownish powder) is snorted or bombed, it has an effect similar to ecstasy causing mood enhancement and hallucinations. Onset of action is usually within one hour and the effects are then almost immediate, perhaps a minute or so. The high lasts about six hours with a peak of two hours. It may cause hyperthermia, paranoid ideation and panic attacks.²

Cathinone is a naturally-occurring beta-ketone amphetamine analogue found in the leaves of the khat plant. Other synthetic cathinones such as methcathinone and MDVP (methylenedioxypyrovalerone) produce similar effects. Beta-ketone refers to the possession of a ketone group in the beta position of the aminoalkyl chain attached to the main molecular methylenedioxyphenyl ring.

Synthetic cannabinoids share some functional similarities with Δ9-tetrahydrocannabinol (THC), the active principle of cannabis. Like THC, they can have sedative, depressant and hallucinogenic effects. They have been detected in herbal smoking mixtures such as ‘Spice’ as well as resins that mimic cannabis resin.

Khat (Catha edulis)

Some knowledge of this plant is necessary in order to explain the background to many of the synthetic designer drugs. Khat is an evergreen shrub the leaves of which are chewed for their stimulant properties. An understanding of its chemical composition helps to explain the use of its constituents in the formation of designer drugs. Khat contains more than 40 alkaloids as well as many other compounds. The khat pheylalkylamines consist of cathinone, cathine and norephedrine: these alkaloids are structurally related to amphetamine and noradrenaline. Although similar to methylamphetamine, methcathinone (variously known as Cat, Kat, Qat, Ghat, and Chat) possesses a chemical structure resembling cathinone; its side effects and addictive properties are more potent.

The plant is chewed into a ball and kept in the cheek for a while. When khat leaves dry, cathinone (benzoylethanamine) decomposes within 48 hours leaving behind the milder chemical, cathine (a phenethylamine compound). Therefore, to maintain the potency of the drug, harvesters transport khat by packaging the leaves and stems in plastic bags or wrapping them in banana leaves to preserve moisture. It is common to sprinkle the plant with water or use refrigeration during transportation. Khat is therefore best used within 12-48 hours when the leaves are still moist.

Catha edulis is a flowering plant (one that produces seeds) native to the Horn of Africa (Eritrea, Djibouti, Ethiopia and Somalia) and the Arabian Peninsula. In these countries chewing the leaves and stalks is a social custom dating back thousands of years. It may take 7-8 years for the shrub to reach its full height (6-12 feet or more). Globally it is estimated that some 10 million males (usually) use khat on a daily basis.

Cathaedulis leaves containa beta-ketone amphetamine analogue. Ketones contain a carbonyl group (C=O) bonded to two other carbon atoms. Phenylalkylamines (derived from phenethylamine) are often termed “bk-amphetamines” for the beta-ketone moiety.

The principal active components in khat are cathinone and cathine. By chewing khat these substances are secreted into saliva. The effects are similar to amphetamine though less potent. Psychological dependence does occur in some though generally khat is not addictive. It is freely available in many countries and its production, sale and consumption are legal, including the Horn of Africa. In the Arab Peninsula it is known as Arabian tea and in South Africa it is referred to as Bushman’s tea.

Although its stimulant effect was originally attributed to cathine, extracts from fresh leaves of khat were shown to contain cathinone, isolated in 1975 and its properties recognized in 1978. Cathinone is not very stable and breaks down to produce cathine and norephedrine which belong to the phenylpropanolamine family, a subset of the phenethylamines and the catecholamines adrenaline and noradrenaline.

When the leaves are chewed the active ingredients are absorbed through the oral and gastric mucous membranes. The action of cathine and cathinone on the reuptake of adrenaline and noradrenaline results in the wakefulness associated with amphetamine derivatives. The effects of cathinone peak after 30 minutes, with nearly 98% of the substance metabolized by the liver into noradrenaline. Cathine has a half-life of about three hours in humans. Typically, an individual consumes 100–200 g of khat leaves (one bundle) in a session, and its effects last for several hours.

Symptoms are rather similar to the ingestion of strong coffee or amphetamines, for example, overtalkativeness and hyperactivity. The effects of oral cathinone occur more rapidly than those of amphetamine, 15 minutes compared to 30 minutes respectively. Khat causes constipation, dilated pupils (mydriasis), tachycardia and increased blood pressure, reflecting the sympathomimetic effects of the drug. Withdrawal symptoms, as would be expected, include mild depression and irritability, lethargy, rebound anxiety causing nightmares, tremulousness and loss of appetite. Long-term use may cause hepatic dysfunction, a permanent greenish tinge darkening of the teeth, and diminished libido. Rarely, dilated cardiomyopathy and myocardial infarction result from chronic use. ³

Mephedrone

Mephedrone (‘meow meow’) is a synthetic stimulant chemically related to cathinone, the psychoactive substance present in the khat plant. It is usually sold as a white crystalline or off-white-yellow powder (as a hydrochloride salt) for about £10 per gram. Consumption is usually oral or intranasal and rarely, by injection. Sellers avoid attracting the attention of regulatory bodies by labelling the substance “not for human consumption,” which means that no advice on safer use and dosing is provided.⁴

In one study the most commonly seen drug class were piperazines, followed by the cathinones, with significant variation in the content in one quarter of these compounds. The authors stated that it was relatively easy to purchase a number of legal highs from different Internet suppliers, though there times when not all of the products were available leading to the problem of users buying different active drugs to those they are used to, raising the prospect of potential toxicity to unknown agents.⁵A cross-sectional survey of 947 of mephedrone users found it to be the sixth most frequently used drug in the previous month after tobacco, alcohol, cannabis, cocaine and MDMA. Users typically were young males; 15% reported using weekly or more frequently; nearly 50% used between 0.5 and 1g during a typical session; intranasal use was the most common route of use (70%). Almost 55% of those who used cocaine reported that the ‘high’ obtained with mephedrone was better: intranasal use was also more likely addictive than oral use. Mephedrone appears to be the most widely abused synthetic cathinone in Europe, in contrast to the USA where MDVP and methylone are the most frequently abused. ^{6 7}

Classification of mephedrone has had a limited effect on controlling its availability and use. Before the introduction of the legislation users generally obtained it via the internet. Now it is bought from street dealers, on average at double the price. Mephedrone was defined as a Class B drug under the Misuse of Drugs Act (1971) in the UK in April 2010. ⁴

Mephedrone produces similar effects to ecstasy, amphetamines and cocaine. It is detected in 20% of ecstasy tablets. It simulates the release of and inhibits the reuptake of monoamine neurotransmitters. The onset of psychoactive effects after insufflation is usually 10–20 minutes with an expected duration of effect of 1–2 hours; after oral ingestion onset is about 15–45 minutes with duration of 2–4 hours, and intravenous users report symptoms peaking at 10–15 minutes with a 30-minute duration of the desired effect.

Mephedrone users report that it has a better quality high than cocaine. It is speculated that mephedrone’s popularity reflects dissatisfaction with the purity and consistency of available cocaine and ecstasy. Concerns are also raised when it is considered that mephedrone is readily available from street dealers and may be taken by young people who have little previous experience of drug use.

Blood or plasma mephedrone concentrations are expected to be in a range of 50–100 μg/l in persons using the drug recreationally, >100 μg/l in intoxicated patients and >500 μg/l in victims of acute overdose.

Mephedroneinduces a greater increase in dopamine than serotonin release whereas MDMA (‘ecstasy’) induces a huge increase in serotonin with an insignificant rise in dopamine. Amphetamine results in a surge in dopamine release with an insignificant increase in serotonin. Mephedrone, amphetamine, and MDMA have decay values of 25, 50 and 300 minutes respectively. Therefore, the rapid rise and fall of dopamine levels could explain the addictive properties of mephedrone in some users. The effects are often described as somewhere between ecstasy and cocaine. As with cocaine, the ‘high’ generally lasts around an hour before wearing off. Furthermore, prolonged high –dose use of the substances can produce long-lasting neurotransmitter deficits in humans. ^{8 9}

According to Mixmag (the online drug-use clubbing survey magazine for the UK) published in March 2012, 42% of clubbers had tried mephedrone the drug, and 34% had taken it in the last month. Some 30% of mephedrone users had reported using more ecstasy since the ban came into effect, while 19% reported using more cocaine. Blood or plasma mephedrone concentrations are expected to be in a range of 50–100 μg/l in persons using the drug recreationally, >100 μg/l in intoxicated patients and >500 μg/l in victims of acute overdose.

In 2011, Mixmag and the Guardian newspaper which draws on previous Mixmag surveys collected 15,500 responses from around the world, mostly the United Kingdom. In 2010/11, reported levels of use of mephedrone in the last year and last month were three times higher among clubbers (30 % and 13 %) than non-clubbers (10 % and 3 %).

Mephedronepredictably, causes increased alertness, restlessness, euphoria, excitement, the urge to talk, openness, time rushes, hot flushes, increased libido and elation. Hyperhidrosis, headache, palpitations, a Raynaud–type syndrome, and nausea are other relatively common unpleasant effects. Dizziness, hallucinations, panic attacks, and psychosis may occur. Other physical symptoms include dry mouth, blurred vision, and epistaxis. Symptoms of intoxication include agitation, aggression, violence, seizures and hyperthermia. Fatigue and insomnia are common residual effects. Mephedrone is generally used by nasal insufflation or ingestion of powder, liquid, capsule or tablets. The majority of users source mephedrone from street level dealers.¹⁰ Mephedrone induces strong feelings of craving in most users. If the unstable ecstasy market situation persists, the potential of mephedrone to substitute for MDMA might be substantial. Mephedrone, sold as ecstasy, is therefore more likely to be a cause for concern in the future.

Bath salts

This is the street name for substances which contain synthetic cathinone stimulants, such as methylenedioxypyrovalerone (MDPV) and mephedrone.¹¹Bath salts components act synergistically at the dopamine transporter site and enhanced dopamine transmission may increase the potential for abuse. MDPV is consumed with other illicit drugs of abuse. It is the primary ingredient in "bath salts." Being a synthetic, cathinone-derivative it produces a high similar to cocaine or methamphetamine. It can be administered orally, by nasal insufflation, smoking, intravenously/intramuscularly, or per rectum, and intoxication lasts many hours.

MDPV may cause cardiac problems and disturbance of perception. During the withdrawal period after MDPV use, bone and muscle pain, and visual disturbances may occur. In the metabolism of MDPV, the most important catalyst is the CYP2C19 isoenzyme; the CYP1A2 and the CYP2D6 isoenzymes also play a role. The formed catechols are conjugated with either glucuronic acid or sulphate.

These compounds are not true bath salts in the traditional sense of household products. Cathinone is an amphetamine-like stimulant found naturally in the khat plant, described in more detail below. MDPV is much more potent than cocaine and its effect is longer lasting.¹²

Because of the sympathomimetic activity side effects are predictable and include cardiac arrhythmias, hypertension, arrhythmias, and hyperthermia. Chest pain, myocardial infarction, sweating, rhabdomyolysis, seizures, stroke, cerebral oedema, cardiorespiratory collapse, and rarely, death, have been reported. Psychiatric manifestations include hypersomnia, panic attacks, agitation, paranoia, suicidal ideation, self-mutilation, and aggressive behaviour.

The mode of action is thought to be the result of disruption and interference with central monoamine systems. In other words, synthetic cathinones increase extracellular monoamines by blocking transporter reuptake and increasing presynaptic neurotransmitter release. The dopamine (DA) transporter (DAT) and serotonin (5-HT) transporter (SERT) tightly regulate the amount of neurotransmitters within the synaptic cleft. Monoamine release also may be driven by presynaptic input from cholinergic or glutaminergic systems.^{12 7}

Psychoactive bath salts are sold as tablets, capsules, or powder and purchased in places such as tobacco and convenience stores, gas stations, head shops, and the Internet. Bath salts may mimic cocaine, lysergic acid diethylamide (LSD), methamphetamine, or MDMA. The most common bath salts are the cathinone derivatives MDPV, mephedrone and methylone. The drugs have the potential for addiction because they cause intense stimulation, euphoria, elevated mood, and a pleasurable "rush". ^{13 14}

In the United Kingdom (UK) to avoid being controlled by the Medicines Act, legal highs are sometimes described as bath salts, fertilizer (plant food), or incense, even though they have never been used for these purposes. In other words, legal highs are not covered by current drugs laws yet are used by individuals in the same way as illegal drugs such as cocaine or cannabis. The easy availability of legal highs marketed as "bath salts", ‘incense’ and ‘plant foods’, with the added proviso that they are not to be consumed by humans allows the drugs to circumvent current legislation. When legislation is changed the molecular structure is easily altered to produce a new legal high.

Synthetic cannabinoids

Marketed as ‘incense’ and labeled “not for human consumption”, these drugs were increasingly popular with students and young adults being initially legal and easily available from stores, online, head shops (outlets selling drug paraphernalia/counterculture magazines) and petrol stations. The structure of synthetic cannabinoids does not resemble that of tetrahydrocannabinol (THC] contained in marijuana or hashish, yet the drugs affect individuals in the same manner and are much more potent. Synthetic cannabinoids are sold under countless names such as ‘Mr Nice Guy,’ ‘Spice’, ‘Sabbaba’ and ‘Lemon Grass’, to name a few. Spice is a designer drug derived from herbs sprayed with synthetic chemicals which mimic the effects of cannabis. The ingredients are thus similar to but not identical to THC. Synthetic cannabis can precipitate psychosis, especially in individuals with a previous history and a chronic psychotic disorder may persist in some vulnerable patients.

A great variety of synthetic cannabinoids, most often cannabicyclohexanol, are used in an attempt to avoid prosecution. Some are sold in 'herbal' smoking mixtures and the latter have been found on occasion not to contain any synthetic cannabinoids at all. Cannabicyclohexanol is a cannabinoid receptor agonist drug. It has been sold under various brands such as Black Mamba, Bombay Blue, Fake Weed, Genie, Bliss, Blaze, Yucatan Fire. Spice products sometimes sold as “incense,” more closely resemble potpourri. Although Spice is usually smoked, sometimes individuals mix it with cannabis or prepare a herbal infusion for drinking.

To create the herbal products, synthetic cannabimimetics are dissolved in an organic solvent (e.g. acetone) and the resulting solution is sprayed on plant material. The doped plant material is then dried and smoked in a similar fashion to actual cannabis. Spice products typically have a pleasurable smell and taste. They are often referred to as herbal or legal highs because of their legal status and ‘natural’ herbal make-up. They are distributed in the form of dried leaves or resin, and powder, and are sold without age restriction in metal-foil sachets, usually containing 3 g of vegetable matter, to which one or more of the synthetic cannabinoids have been added. Spice is typically smoked, using a pipe or by rolling in a cigarette paper, and can also be ingested as an infusion, or inhaled.^{15 16}

Drugs of the 2C family (phenethylamines containing methoxy groups attached to a benzene ring) have hallucinogenic and stimulant effects. The term ‘2C’^' refers to the 2 carbon atoms between the benzene ring and the amino group in these compounds. The effects are a cross between MDMA and LSD. They are relatively new to the market and not widely available in the UK. An excited delirium presentation seems to be consistent in deaths attributed to 2C drugs and at least five deaths have been reported in the literature in patients intoxicated with 2C drugs. One agent known as 2C-1 or Smiles, which first appeared in 2003,has more potent effects than MDMA and LSD. Users report an intense energy with vivid visual and auditory hallucinations lasting hours to days.^. Patients may exhibit symptoms consistent with serotonin toxicity. Doctors need to be vigilant as synthetic drugs do not show up on routine testing. Treatment of 2C intoxication is primarily supportive.¹⁷

Despite widespread Internet availability, many of these drugs remain unfamiliar to doctors and yet ‘bath salts’, have resulted in nationwide emergency department visits for severe agitation, sympathomimetic toxicity, and death. As with other illicit substances designer drugs may compromise cardiac function causing hypertension and tachycardia and users who inject run the well-known risks of contracting hepatitis C or HIV, thrombophlebitis and embolus formation.

Methoxetamine

Methoxetamine (also known as ‘mexxy’) is available on the Internet and marketed as ‘legal ketamine.’ It is an arylcyclohexylamine chemically related to ketamine and PCP (phencyclidine). Methoxetamine is longer acting and more potent than ketamine. The drug, a white powder, is usually taken sublingually, snorted, ‘bombed’, or injected intramuscularly. Doses are typically between 5mg-90mg orally. After snorting the drug it may take 30-90 minutes for its effects to become apparent. When injected the onset of action is usually within five to ten minutes. The overall duration of effect is within the range of 1–3 hours, sometimes longer. The drug induces feelings of detachment (dissociative state), paranoid symptoms, visual hallucinations, restlessness and increased energy in some. Other reported symptoms include confusion, catatonia, depression, tachycardia and hypertension. Methoxetamine is now a Class B drug under the Misuse of Drugs Act.^{18 19}

Piperazine derivatives

The piperazine derivatives, a class of amphetamine-like compounds that includes BZP (benzylpiperazine) and TFMPP (trifluoromethylphenylpiperazine) are making a comeback as "legal ecstasy." Often perceived as safe by the public, adverse effects may range from minimal to life-threatening. Co-ingestion of BZP and TFMPP causes increased action of dopamine and serotonin, similar to MDMA. Severe symptoms include seizures, hyperthermia, hyponatremia, dystonic reactions, rhabdomyolysis, renal failure, metabolic acidosis, DIC, and respiratory failure. ²⁰ Over the last few years piperazine derivatives are being sold as ecstasy pills, or under the names of “Frenzy”, “Bliss”, “Charge”, “Herbal ecstasy”, “A2”, “Legal X” and “Legal E”. Although piperazine designer drugs enjoy a market reputation of being safe, they may cause distorted perceptions after ingestion. There are several reports of toxic symptoms experienced by users after drug intake.The piperazinic compounds are derived from piperazine, a cyclic molecule containing two opposite nitrogen atoms and four carbon atoms distributed between the two and were originally used as anti-helminthic agents in the 1950s. Designer drugs of this class can be divided into the benzylpiperazines such as benzylpiperazine (BZP) and its methylenedioxy analogue methylenedioxybenzylpiperazine (MDBP), and phenylpiperazines such as chlorophenylpiperazine (CPP), trifluoromethylphenylpiperazine (TFMPP), and methoxyphenylpiperazine (MeOPP). A third group includes the thienylmethylpiperazines. Chlorophenylpiperazine is an active metabolite of drugs such as trazodone, and nefazodone used as antidepressants. A survey in the UK found that piperazines are among the most common active drugs in tablets purchased from internet supplier sites.Piperazine-derived compounds are therefore emerging designer drugs, whose abuse has increased remarkably worldwide.²¹

Naphyrone

Naphyrone(naphthylpyrovalerone) or NRG-1 (or Energy1) is a cathinone derivative available to buy on a number of websites and is gaining popularity. It is sold as an alternative to mephedrone. Belonging to the designer drugs class, it is similar in structure to pyrovalerone, a monoamine uptake inhibitor and as it is somewhat similar to other cathinone derivatives it has the potential to produce anxiety, paranoia, and cardiovascular side effects. Two products, both sold as NRG-2 from different internet suppliers, were found to contain the banned substituted cathinones - 4-methylethcathinone (4-MEC) and 4-methylmethcathinone (4-MMC), the latter being present in much smaller quantities. Although sold as research chemicals and labelled 'not for human consumption', they are essentially legal highs and are available online. ^{22 23}

Table 2: Some commonly used psychoactive substances

Discussion

New designer drugs have increased in popularity over the past several years because of their euphoric effects. Understanding the pharmacology and toxicology of these agents is essential in order to provide the best medical care for patients. They are all potentially dangerous. For example, an excited delirium presentation seems to be consistent amongst deaths attributed to 2C drugs.

From the above description it can be seen that synthetic drugs fall into three broad categories: synthetic cathinones (bath salts), synthetic cannabinoids (spice or incense), and amphetamine-like drugs (methamphetamine, ephedrine, MDMA). Cathinones being related to the amphetamine family will cause dilated pupils, hypertension, hyperventilation, paranoia, agitation, hyperthermia, tremors and seizures. Many countries have made certain cathinones illegal, for example, mephedrone, methylone and MDPV. Indeed, the robust stimulation of dopamine transmission by MDPV predicts serious potential for abuse and may provide a mechanism to explain the adverse effects observed in humans taking high doses of 'bath salts' preparations. Furthermore, pyrovalerone is much more potent than cocaine at inhibiting the uptake of dopamine and norepinephrine.

Methcathinone was previously used in Russia as an antidepressant, also known as “Cat” and “Jeff” when used recreationally. Nowadays the drugs are sold as bath salts, plant food, insecticides, chicken feed additives, or research chemicals with names such as like NRG (Energy) and meow, meow. Bath salts are water-soluble, usually inorganic, solid products designed to be added to water during bathing. Numerous nicknames are used to describe them including Ivory Wave, Purple Wave, Red Dove, Zoom, Bloom, Cloud Nine, Ocean Snow, Lunar Wave, Vanilla Sky, White Lightning, and Hurricane Charlie.

Although ‘legal highs’ are commonly referred to as bath salts they are not Epsom salts (magnesium sulphate) or other water softeners within the usual meaning. In many cases the chemical ingredients are changed without the consumer knowing, making risks unpredictable. Some legal highs contain active ingredients controlled under the Misuse of Drugs Act 1971 (UK). Therefore any individual found in possession of these products would be liable to prosecution and the associated penalties, even if unaware that he/she has purchased a controlled drug. However, claiming a product to be "not intended for human consumption" can potentially circumvent the entire legal process. Drug designers are already showing skilful exploitation of the law and remain far ahead of criminalization efforts. Furthermore, the irony of prohibition is that the supply and slump in the market for cocaine and ecstasy in 2009 led to individuals resorting to untried and untested substances that are now easily available online. ^{24 25}

Synthetic cathinones are mostly excreted via the urine and can be measured via gas or liquid chromatography-mass spectrometry in the blood, urine and stomach contents. They can also be analysed in hair. Unlike traditional cosmetic bath salts, which are packaged and sold for adding to bath water for soaking and cleaning, synthetic designer drugs sold as "bath salts" have no legitimate use for bathing and are intended for abuse. Baths salts contain one or more synthetic derivatives of the naturally-occurring stimulant cathinone. Low doses produce euphoria and increase alertness, but high doses or chronic use may cause serious adverse effects.²⁶

Treatment

Treatment should be tailored to the specific drug of abuse. Medical and psychological needs require examining. Generally, treatment uses a combination of counselling and medication to reduce the need or desire (craving) for the drug and give the person the skills to refrain from future drug use. Other treatments might include cognitive behavioural therapy, detox, and relapse prevention techniques.

Supportive care is the mainstay of treatment for untoward serious side effects. Sedation with benzodiazepines is indicated for agitation, seizures, tachycardia, and hypertension. Extreme hypertension that persists despite benzodiazepines may be treated with vasodilators. Beta blockers should be avoided due to the potential to cause unopposed alpha-adrenergic stimulation, worsening the hypertension. Significant hyperthermia may require passive or active cooling. All moderately to severe symptomatic patients should have an electrocardiogram (ECG), be placed on a cardiac monitor, and receive serial temperature checks. Electrolytes, liver function tests, cardiac enzymes creatine, and toxicology should be carried out. Asymptomatic patients with no other suspected ingested drugs or psychiatric symptoms generally may be discharged.

Prevention

Banning legal highs is probably futile because it is impossible to keep up with newer drugs because they are synthesized as soon as the ‘illegal’ drug becomes banned. Some would argue that arresting users creates more harm for individuals, their families and society, as they are then caught up in the criminal system. Others may argue that ‘legal highs’ are not generally harmful and not as dangerous as opiates or their derivatives, or indeed alcohol. It might be more worthwhile making legal highs ‘uncool’, much in the same way that cigarette consumption is now frowned upon. However, it would require a great deal of public money to subsidise such an advertising venture.

Users of legal highs need to be made aware that such drugs purchased on-line may contain illegal substances and therefore may render them subject to prosecution if found in possession. ²⁷

Pre-school family based programmes, and programmes involving the school and community, motivational interviewing for adolescents, and individual programmes, may be beneficial in reducing drug use and other harmful outcomes. Importantly, none of these approaches focus exclusively on particular substances or groups of substances, and although there have been relatively few investigations of intervention processes they most likely work by targeting a number of important precursors of drug use behaviour.²⁸

Preventing designer drug abuse begins with understanding the warning signs of addiction which in many respects are similar to alcohol or more common street drugs.

Club drugs are now widely available and their harmful effects are increasingly becoming more evident. Their effects are unpredictable as they are often ‘contaminated’ with other harmful substances. It is unlikely that legislation will have a meaningful impact. Increasing public awareness about these drugs is paramount, and medical and nursing staff should consider intoxication in those patients who present with agitation and psychosis who have no previous history of mental health problems.

Pharmacists are in a pivotal position to observe changes in patterns of drug use and report worrying trends to health care practitioners. Counselling for young people especially and prevention programmes based in schools could prove useful in pointing out the dangers of these drugs to teenagers. Health care professional too should endeavour to keep up with recent information on these substances by attending hospital-based lectures or conferences as part of continuing professional education.

Urine drug testing will generally be unhelpful as many club drugs are undetectable on standard urine drug screens.²⁹ Mental health staff should enquire about club drugs as part of routine drug and alcohol assessment and be aware that these patients may not fit the stereotype of a drug misuser.

Introduction

Driven by a global rise in opioid dependence, Opioid Substitution Treatment (OST), the prescribing of opioids (usually methadone or buprenorphine) as maintenance treatment, has expanded worldwide over the last two decades³. Participation in OST reduces the risk of death by overdose⁴, reduces the risk of HIV transmission⁵ and reduces participants’ involvement in property crime⁶. For these reasons, maintenance with methadone remains the major public health response to reduce the harms caused by heroin addiction.

In the United Kingdom (UK) in the late 1990s, government funding to expand access to OST was provided, with the explicit objective of reducing crime⁷. The expansion of treatment was supported with clinical guidelines², and targets were set to try to ensure good outcomes. Given the research evidence on the importance of retention in producing better outcomes, service providers were set a target of retaining at least 75% of people in treatment for 3 months. A tool to monitor outcomes, the Treatment Outcomes Profile (TOP)⁸, was developed and service providers nationally were set a target of 80% of people in OST completing TOP at entry and after 6 months⁹. This 20-item self-report questionnaire records a set of core data for the previous 28 days, including the number of days on which heroin and cocaine have been used. 

The amount of methadone prescribed in England and Scotland increased fourfold over the decade 1998 – 2008³. However, in 2010, Britain’s newly-elected government signalled a change in the direction of drug policy¹. The paradigm on which the new policy is based is “recovery”, a concept embracing self-help, mutual support, and optimism about the possibility of positive change. The policy is in part driven by the perception that treatment services have a defeatist attitude, expecting little positive change – hence the claim that there are too many patients “parked on methadone”. To counteract this perceived pessimism, the “recovery agenda” includes incentives to services to promote abstinence from all drugs including prescribed OST medication. This policy has been criticized as being inconsistent with the available evidence¹⁰, but has been defended on the grounds that many patients on methadone were doing poorly, and needed encouragement to make positive changes in their lives.

In 2010, we decided to investigate to what extent people were responding poorly to treatment, and whether this could be improved by implementation of evidence-based treatment.

Methods

This quality improvement project was undertaken in two OST clinics in Merseyside, managing in total over 1000 patients. The services had the same senior leadership and medical staff, but separate teams of nurses and key workers. Supervised administration was provided by local retail pharmacies.

In October 2010 key workers were provided with list of patients currently under their care and asked to identify patients they thought were using heroin regularly.  A research assistant then checked case notes of identified patients, looking at self-reported heroin use as recorded in TOP monitoring forms, and at the results of previous urine toxicology tests. Those whose most recent TOP was performed at entry to treatment were excluded (since their self-reported heroin use covered a time when they were not in treatment). Among the remainder patients reporting use of heroin on at least 8 days in the 4 weeks preceding their last TOP interview were classified as “non-responding” patients. The case notes of all identified “non-responders” were reviewed using an audit tool covering age, sex, postcode, date of entry into treatment, duration of treatment, dose of medications, extent of supervised administration, dates and results of recent urine toxicology, and date and self-reported drug use from previous TOP questionnaires. This data was collected at baseline and again at re-audit (follow-up) 9 months later.

Postcodes were used to derive Index of Multiple Deprivation (IMD) scores¹¹. The English index of multiple deprivation (IMD) is a measure of multiple deprivations, with domains including employment deprivation, health deprivation and disability, education skills and training deprivation, barriers to housing and services, living environment deprivation, and crime.

In one clinic, the “implementation clinic”, beginning January 2011, key workers were asked to refer all non-responders for a medical review. Patients were also screened for comorbidity, taking advantage of a separate project running concurrently which was designed to test the psychometric properties of a new questionnaire on mental health and well-being. All service users at the implementation clinic were invited to take part. The study had National Research Ethics approval and approval from the Merseycare NHS Trust R&D Office. Quality of life was assessed with the EQD¹² which comprises 5 domains measuring health-related quality of life: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Depression was screened for with the Beck Depression Inventory¹³.

UK guidelines recommend for patients doing poorly “..ensuring medication is provided within evidence-based optimal levels, changing to another substitute medication, increasing key working or psychosocial interventions and increasing supervised consumption” ³. The recommended dosage for effective treatment is listed as in the range 60-120mg/day of methadone. At medical review, the plan was for the doctor to assess the non-responding patients, and propose raising methadone dose progressively until heroin use ceased, or a maximum dose of 120mg/day was reached; and requiring supervised consumption of methadone for patients persisting in heroin use.

Establishing the medical reviews in one of the two clinics was necessary for logistic reasons, but it also allowed an opportunity to assess the impact of the reviews, by comparing the outcomes of non-responders in the two clinics. If effective, it was proposed to extend this approach to the second ‘treatment as usual’ service. Referrals for medical review ceased in June 2011, and over the next three months staff feedback about the process was sought. In October 2011 a repeat audit of case notes including TOP results of all previously identified non-responders at both services was undertaken.

At follow-up data on the frequency of medical appointments in the preceding 6 months were also collected. In cases where people had left treatment, the TOP performed on exit from treatment was used. Those non-responders who had left treatment were identified and tabulated according to the reason for leaving treatment.

Flowchart 1: The audit and re-audit process

Ethics

The audit was approved by the local NHS Trust R&D Office. Funding was obtained to undertake the work by Mersey Care NHS Trust.

Analysis

Data was entered into SPSS version 18 (for windows). Summary statistics and standard hypothesis tests compared non responders in the intervention service to non responders in treatment as usual to ensure there were no statistically significant differences between the two groups at baseline. Chi-square and t-tests compared age, sex distribution, IMD scores, methadone dose and months in treatment this episode.  Mann-Whitney U tests compared the number of TOP forms completed in each group during the previous 6 and 12 months. Regression analysis explored whether there was a relationship between attendance for supervised administration, self-reported quality of life and depression for non responders in the implementation group. Differences in baseline and at 9 month re audit methadone dose and heroin use were tabulated for each group. Mann-Whitney U-tests compared any differences between the two groups.  Differences within each group were also compared using the Wilcoxon signed ranks test.

Results

The implementation service managed 534 patients, of whom 130 (24%) were initially identified as non-responders, reporting heroin use on 8 or more days in the previous month at their last TOP interview. At the TAU service there were 485 patients, of whom 112 (23%) were identified as non-responders. Of the 242 non-responders in total, 67 (28%) were new to treatment, and were excluded. This is illustrated in the flowchart 2.

Flowchart 2: Sample Algorithm

Approximately 50% of the non-responders in each group reported daily heroin use at baseline.  The two groups of non-responders did not differ significantly in terms of age, sex distribution, nor on the Index of Multiple deprivation scores (mean of 62 reflecting very severe social exclusion across both groups). Non responders in the implementation service had been in treatment a median of 18 months compared to 17 months for those in treatment as usual. Urine testing was performed infrequently in both services, but a result was available from the six months prior to baseline for 133 of the remaining 175 subjects. The urine tests results were broadly consistent with the patients self-report. Aspects of treatment at the two services differed, as shown in Table 1. At baseline, doses did not differ significantly, but the treatment as usual group was significantly less likely to have their methadone administration supervised, and had less frequent TOP monitoring.

Table 1 Profile of non-responders and their treatment at baseline

Despite almost all non-responders being booked in for an appointment and given reminders at the implementation service, only 47 (45%) of the 104 identified attended at least one medical review. Keyworkers commented that the main reason for non-attendance was that clients were quite happy continuing heroin use and did not see stopping as something they wanted to do. When patients were told they would only receive their prescription renewal after attending, some patients chose to go without methadone and make contact a few days later, rather than attend an appointment. Among those who did attend, there was frequently resistance to increasing their methadone dose, and anger at the suggestion that medication administration should be supervised. Word of mouth spread through the service that doctors were proposing dose increases and more supervision. This increased resistance among patients, and appears to have generated some resistance among keyworkers, some of whom saw their role as advocates for the patients.

The attempt to implement change in one clinic appears to have had small effects in increasing average doses there, and having more patients seen by a doctor. Between baseline and 9 month re-audit (follow-up), mean methadone doses increased in the implementation group and fell in the TAU group, as shown in Table 2. There was a small and statistically significant increase in methadone dose in the implementation group compared to the TAU group. The difference in change in methadone dose between the two groups was statistically significant (Mann-Whitney U= 2745, p=0.002), but the mean dose increase (3mg) in the implementation group was small. In the 6 months prior to the collection of follow-up data, medical reviews in both services were infrequent; 36% of patients in the implementation group and 66% of patients in the TAU group had not seen a doctor in their OST service (Chi square =13.38, df=1, p=0.001).

In both groups, the reductions in heroin use over time were statistically significant (Wilcoxon signed ranks test p = <0.05), but the change in heroin use over time did not differ significantly between the two services (Mann-Whitney U 2832.5, p=0.7). The changes from baseline audit to 9 month re audit are shown in Table 2. Among the 47 patients who attended a medical review, the mean prescribed methadone dose rose from 58 to 66mg/day, but the number receiving supervised doses actually fell, from 23 at baseline to 20 at follow-up. Mean days of reported heroin use fell from 20 to 12 (6 patients reported abstinence) – changes almost identical to what was observed in the TAU group.  

Table 2 Changes in dose and heroin use between baseline (T1) and follow-up/re audit (T2)

29 non responders (28%) from the implementation service, and 27 (38%) from the TAU service had left the service between baseline and 9 month re audit. Most discharges (31/56) were transfers to another service as part of a local policy to move more people into treatment in primary care. Eight patients from the Implementation service dropped out of treatment, and 4 patients from the TAU service did so. Differences in the pattern of leaving the two services did not approach significance.

Table 3 Reason for discharge

44 non responders who attended a medical review at the implementaion service  completed questionnaires on health, quality of life, and depression. Ninety-six percent were not in education, employment or training (NEET). On the Beck Depression Inventory, 50% of respondents reported depression in the moderate to severe range. Regression analysis indicated that having to attend for supervised doses was associated with less depression measured on the BDI (r=-.332, p=0.039), and with better quality of life in terms of EDQ scale of self-care (r=-.598, p<0.001) and being able to undertake usual activities (r=-.605, p<0.001).

Discussion

Many people persisting in heroin use were receiving care that was out of line with guidelines – doses below 60mg, often with no supervised doses, and seldom attending for medical reviews. However, the attempt to systematically implement guidelines was not effective. Most patients did not attend, and many of those who did attend resisted changes. Although patients who attended received slightly higher doses, changes in heroin use in the subset who actually attended for review were no different to the changes observed in the TAU group.

Higher methadone doses, and patients having control over their doses, have been shown in a meta-analysis to be independently predictive of better outcomes¹⁴. One possible explanation for the failure to implement guidelines is that it may have been perceived as challenging clients’ control over their treatment. If so, it was a challenge easily defeated. Patients clearly had substantial control over their treatment, choosing whether to attend appointments, whether to accept higher doses, and whether to accept supervised doses. However, this degree of control over their treatment did not appear to be beneficial. “Non-responders” reported depression, disability and a poor quality of life.

Guidelines need to move beyond systematic reviews of effectiveness, to include evidence about implementing evidence in a real world setting¹⁵. Our conclusion is that the failure to implement guidelines was that the approach adopted was not congruent with clinic culture, which emphasised “support” rather than “structure”. “Structure” refers to both cognitive and behavioural elements of treatment.  The cognitive elements are defined and agreed objectives, a sense of the direction and purpose of treatment. In all areas of mental health, clinical interactions are most useful if focused on specific performance goals related to the patient’s circumstances¹⁶.  In the OST services studied, there appeared to be a focus on process and on supporting patients, rather than achieving outcomes.

Structure also includes behavioural elements - expectations and rules regarding attendance, and daily attendance for supervised administration. Interviews with UK patients in OST have indicated that they understand and value the role of supervision, not only in minimizing diversion and misuse, but in providing an activity for many people without social roles¹⁷. Consistent with the benefits of supervision, in the current audit more supervision was associated with less depression and less-poor quality of life.

This audit had several limitations. It did not attempt to measure the proportion of patients responding poorly to long-term methadone treatment, and it is possible that the true proportion may be higher than the 17% identified by key workers. Documentation of treatment outcomes, using TOP reports and UDS results, was unsystematic, limiting the number of patients in whom complete data was available. “Non-responders” self-reported heroin use to keyworkers, who administered the TOP questionnaire, and there may have been under-reporting. However, while this study may not have identified all non-responding patients, this does not invalidate the observation that attempting to implement guidelines was not successful.

Most importantly, the observations from these clinics may not be generalisable to other treatment settings. However, certain key data are available suggesting the treatment and outcomes observed in this study were not atypical. A report on national TOP monitoring noted patchy availability of follow-up data, and confirmed a high rate of persisting heroin use in treatment, with 38% of participants reporting abstinence from heroin¹⁸. Despite this high rate of heroin use, a recent survey reported a mean dose of 56mg of methadone in a national survey¹⁹. In this regard, the clinics in this report thus seem representative.

Medical staff appeared to have a peripheral role in delivery of OST in these clinics. Most non-responders did not have a medical review in 6 months – despite persisting heroin use, and self-reported depression. In the 1980s in the US, methadone treatment underwent a process labelled “demedicalisation”, marginalisation of the role of medical practitioners, and a loss of the sense that methadone was a medical treatment with clearly defined objectives and guidelines²⁰. This contributed to a situation in which much methadone treatment in the US was out of line with research evidence²¹. The current audit suggests that a similar process of demedicalisation and deviation from evidence-based treatment has been occurring in some NHS services in the UK. 

If these observations are representative of at least some treatment culture in the UK, they lend support to the criticisms made of methadone treatment in the new UK drug strategy¹. To the extent that the recovery agenda challenges clinic culture and shifts the focus of treatment onto outcomes, it is a positive development.

However, many well-intentioned policies have unintended consequences, and there are well-based fears that the new policy promoting abstinence from OST as an objective of recovery will lead to an increase in overdose deaths³. This is specifically because of the risk of overdose deaths after leaving treatment. The reason for the increased risk of overdose after leaving treatment is that newly abstinent addicts who have reduced opioid tolerance, and a dose of heroin they previously used during periods of addiction becomes a potentially fatal dose once they are abstinent. This risk attaches to all forms of drug free treatment, as well as to patients who have left methadone. The critical issue is that lapses to heroin use, and relapses to dependent heroin use, are very common among newly-abstinent addicts. It is the high probability of relapse to heroin use which is the basis of long-term maintenance treatment – better to keep people safe and functioning normally, albeit while still taking a medication, than the risk of relapse and re-addiction, or relapse and fatal overdose. In the UK, implementation of the recovery agenda has included incentives to abstinence, and this is not consistent with evidence about the risk of relapse. If the recovery agenda can accommodate the evidence that indefinite maintenance as a valid option for many, perhaps most heroin users, then the evidence of this study is that far from being in contradiction, the recovery agenda may facilitate the implementation of evidence-based practice. 

Introduction

Grapefruit (Citrus paradise) is thought to have originated as a cross between the Jamaican sweet orange (Citrus sinensis) and the Indonesian pomelo (Citrus maxima) fruit. It was first bred in Barbados and brought to Florida in 1820s. Subsequently, different mutant and hybrid varieties were developed. Although the white and pink varieties were being popularly consumed, the ruby red variety has become very popular and commercially successful.

The taste is a mixture of the sweetness and tanginess of an orange and the sourness of a citrus fruit. It is a rich source of vitamins C and potassium. It is found to have antioxidant properties due to the presence of lycopene¹and an ability to inhibit atherosclerosis due to the presence of pectin^2,3. The seed extract is thought to have antimicrobial and antifungal properties.

With good publicity, marketing and coverage by health magazines, grapefruit juice has gained widespread use and in most Western Europe and America it is one of the common fruit juices consumed at breakfast. In the United Kingdom, in terms of fruit juice sales, it ranks second among citrus fruits and the fourth overall.⁴

Pharmacokinetic effects

The interaction of grapefruit juice with medication was first reported by Bailey et al in 1991 after their accidental discovery of up to four fold increase in the blood levels of filodipine when taken with grapefruit juice⁵. Further studies have identified similar interactions with more than 85 drugs⁶. The half life of the effects of grapefruit juice is estimated to be around 12 hours⁷, but these effects may last from 4 hours to 24 hours⁸. The effects are more pronounced with regular consumption of grapefruit juice prior to ingestion of the drug and there can be a cumulative increase in drug concentrations with continued grapefruit juice intake^7,9.

As little as 200-250ml may be sufficient to induce its effects^7,10. Some of the interactions involve medication that have narrow therapeutic window and can therefore cause potent adverse effects such as torsade de pointes, rhabdomyolysis, myelotoxicity, respiratory depression gastrointestinal bleeding, nephrotoxicity and sudden cardiac death.⁶ There is a lack of awareness among both doctors and patients about its effects and interaction with various medications.

Mechanism of action

These pharmacokinetic interactions with grapefruit juice are more observable in drugs with high first pass metabolism and in those with an innate low oral bioavailability. The oral bioavailability of affected drugs is increased but their half life usually remains unaltered^11,12. Grapefruit juice is associated with the inhibition of Cytochrome P450 enzyme system, particularly the CYP3A4 enzyme⁷. The CYP3A4 enzyme is present both in the liver and intestinal mucosa. Once the drug is taken up by the mucosa, the susceptible drug may be metabolised by the CYP3A4 or pumped back into the intestine lumen by P-glycoprotein. The observed effects of grapefruit juice are thought to be mainly due to the inhibition of intestinal CYP3A4 activity, which leads to decreased first pass metabolism and hence increased bioavailability. This inhibitory action is fairly quick and may be due to the rapid degradation of the enzyme or any decrease in its production from the mRNA. The production of mRNA itself from DNA is not thought to be affected¹³. The susceptibility varies between individuals depending upon their genetic expression of CYP3A4, the effects being more prominent in those with high small intestinal CYP3A4 content^{7, 14}.

The effect of grapefruit juice on the P-glycoprotein is unclear. The activation of P-glycoprotein pumps the drug back into the intestinal lumen which should reduce bioavailability and similarly the inhibition of P-glycoprotein increases the bioavailability. Some studies suggest that the inhibition of P-glycoprotein is the mechanism responsible for the increased bioavailability of certain drugs like cyclosporine^15,16.

The active ingredients responsible for interactions of grapefruit juice with medication are not clearly identified. The compounds exerting this action are thought to be either the flavanoids such as naringin and naringinen^17,18,19,20 or the furanocoumarins such as bergamottin and its derivatives^21,22,23,24, but there is no clear consensus.

Drug interactions

Table 1 below lists some of the commonly used drugs whose bioavailability is affected by grapefruit juice. Although the best known interactions have been mentioned in the table, there are many other drugs like carvedilol, estrogens, itraconazole, losartan and methyl prednisolone whose bioavailibility is increased by grapefruit juice and the adverse effects are not yet clear.

Table 1: Potential risk of drug interactions with grapefruit juice^{6, 7,13,25,26,27}

Implications on clinical practice

Clinicians should make themselves aware and educate their patients of these potential interactions, keeping in mind the individual variations in susceptibility. This may be particularly important for medications that have a very narrow therapeutic window, medication that have an innate low oral bioavailability and a high first pass metabolism mainly via CYP3A4.

A patient may develop exceptional beneficial effects or equally, significant adverse effects should he start consuming grapefruit juice mid- treatment. Conversely, a drop in efficacy of a drug is also possible, should a patient using grapefruit juice on a regular basis, stops it suddenly.

To achieve steady concentration of the medication and avoid such potential effects, it may be best to advise patients to avoid consuming grapefruit juice if there is a potential of interaction. The half life of the effect of grapefruit juice appears to be around 12 hours and therefore, it is advisable to discontinue grapefruit juice 72 hours prior to starting any drug with potential interactions. ^8,9

Due to the prolonged effect of CYP3A4 inhibition which may last up to 24 hours, it is not possible to avoid these interactions by separating the times of drug and grapefruit juice consumption.^8,9

There is more research needed to clarify the mechanism of action and to determine the active ingredients. The identification of the active ingredient can allow oral administration of drugs that undergo CYP3A4 mediated high first pass metabolism because of which currently, they can only be given systemically.

In light of the possible increase in bioavailability of specific drugs, although it might be possible for patients to use this to their advantage in reducing the dose of their medication under medical supervision, it is perhaps too early to recommend the use of grapefruit juice as an adjunctive or augmentation strategy.

Definition

1. Autoimmune disorders (e.g., systemic vasculitides, Goodpasture's syndrome, antiphospholipid antibody syndrome)
2. Pulmonary infections (e.g., invasive aspergillosis, hantavirus infection)
3. Toxic exposures (e.g., trimellitic anhydride, isocyanates, crack cocaine, certain pesticides)
4. Drug reactions (e.g., propylthiouracil, diphenylhydantoin, amiodarone, methotrexate, , nitrofurantoin, bleomycin, montelukast, infliximab
5. Cardiac disorders (e.g., mitral stenosis)
6. Coagulation disorders caused by diseases or anticoagulant drugs
7. Isolated pauci-immune pulmonary capillaritis
8. Idiopathic pulmonary haemosiderosis
9. Bone marrow or solid organ transplantation.