Concord Seminar 22 May 2007
The Interpretation of Urine Toxicology in Dependency Treatment. Principals and Pitfalls
Speaker: Dr John Lewis, Toxicology Unit, Pacific Laboratory Medicine Services
Dear Colleagues,
Dr Lewis is one of the world’s leading experts in drug testing. His speaking manner combines what T. S. Eliot might have termed a lugubrious drollery with a profound grasp on his subject. It is easy to be light-hearted about ‘piss tests’ but it is also deadly serious if your own job, drivers licence or liberty depend upon such a result.
We were reminded first up what urine testing can NEVER determine with any accuracy: (1) the dose, (2) the time it was taken or (3) the pharmacological effect of any substance being tested.
The most common drug assays they perform are for methadone and metabolites, cannabinoids, opiates, cocaine, benzodiazepines and amphetamines. Barbiturates often omitted these days since their illicit use seems to have ceased for all practical purposes. The term ‘amphetamine type substances’ (ATS) is now superseding ‘sympathomimetic amines’. This group includes dexamphetamine, methylamphetamine, ecstasy (MDMA), methylenedioxyamphetamine (MDA), and other ‘designer’ drugs such as paramethoxyamphetamine (PMA) and their metabolites, but also ephedrine, pseudoephedrine. One needs to know the particular immunoassay ‘kit’ being used to be sure what exactly is detected and at what level.
Laboratories are asked to perform tests both in a clinical setting as well as for forensic, workplace or medico-legal reasons. For clinical purposes a cost effective and fast turn-around time approach is used. This starts with an inexpensive immunoassay which is very sensitive for most of the drugs being tested for, but generally not specific. Hence a negative batch of tests can yield a fast, efficient response to the clinician. Positive immunoassay results for any of the drug groups (or negative for methadone) may indicate further testing, typically using GCMS (gas chromatography/mass spectrometry), which is considered the ‘gold standard’. Although thin layer chromatography (TLC) is not commonly used nowadays, Dr Lewis says it still has a place: it presents information on a large range of drugs to view at a single glance, and is inexpensive. Because the TLC depends upon the human factor of recognising patterns, it is subjective and unless the spot patterns correspond to known medication, confirmatory testing by mass spectrometry is usually conducted. Although it is not used for medico legal work, it still has a place in clinical settings, as an adjunct to mass spectrometry in presumptively identifying a wide range of therapeutic substances not amenable to immunoassay.
In particular cases there will need to be specific tests done, especially for suspected drug use which may not be detected by the usual immunoassays. These include tests for doctors, nurses or other health care workers on conditional registration due to drug use. Such drugs include pethidine, tramadol and the short acting anaesthetic propofol. Abuse of these drugs outside the medical setting is exceptional.
Note that buprenorphine is also hard to detect by simple methods. Although there is an immunoassay for the drug, toxicologists must be aware of possible false positives from a number of unrelated therapeutic substances. However, like methadone, when the dose is taken under supervision such testing is less important than, say, in England where much treatment is unsupervised and testing for the prescribed medication can be crucial in determining compliance and overall stability.
Dr Lewis then detailed the limitations and strengths of modern immunoassays in determining a class of drug but only in two cases can they detect specific metabolites, EDDP (for methadone) and 6-mono acetyl morphine (heroin). The value of a negative test was pointed out. We were reminded that testing was almost pointless in hospital casualty cases: for overdoses, the results are usually not available until either the patient is dead or else recovered. Also, medications are used so routinely and such patients may have injuries necessitating local anaesthetics, dressings, iodine, etc in the course of their treatment in the casualty ward that results are close to meaningless.
Specifically, Dr Lewis said that positive opiate and ATS immunoassays should be taken with caution as there are many causes of false positives. These include poppy seeds, cough mixtures, decongestants and common analgesics. Dr Lewis told us that his own urine remained positive for ‘opiates’ for nine days after a dose of the cough suppressant pholcodine. The main value of these screening tests is when the result is negative. Note that ‘opiate’ immunoassays do not detect the ‘opioids’ methadone, buprenorphine, pethidine and others. Oxycodone has only a very weak response to “opiate” immunoassays.
We were then shown the plates used for thin layer chromatography and a list of 20 common drugs which can be definitively determined using this method (eg. morphine, codeine, oxazepam, pseudo-ephedrine, paracetamol and nicotine). GCMS was then described in response to a question from the floor. In essence it appears that there are two properties of each substance which are identified in the method, causing a unique fingerprint from the two derived figures. It is more expensive than other methods, but more accurate and specific, being able to detect both the original base compound as well as ‘derivatised’ products.
Then we had a brief tutorial on the use of testing for alcohol consumption. Everyone knows about breath testing, but 5% of alcohol is excreted in the urine and there is a direct correlation between plasma and urine alcohol concentration of 1.3:1. However, due to the short half life of alcohol, such testing is only of any use within hours of the drug use. And, as with other drugs, a certain level could be associated with a small amount of drug used very recently, or equally, a large amount used quite some time before.
There are also unexpected false positives, including a case Dr Lewis described where urine from a diabetic in a rehabilitation facility had undergone fermentation (probably by yeasts) before being tested; the calculated blood alcohol concentration (0.34) would have been lethal. A less ‘gross’ error might not have been discovered, and this would have led to the automatic expulsion of the person from the rehab facility.
Tests for cannabis are of limited value since, for most, its use is not relevant to the treatment or supervision being given. Hence Dr Lewis only performs cannabis tests when specifically requested, such as in patients being treated for cannabis dependence, to assess progress.
We were then taken through some metabolic pathways. Heroin breaks down within minutes into 6-acetyl morphine, then to morphine. This then is broken down into morphine-6 or -3 glucuronide which are excreted. Codeine is largely conjugated into codeine-6 glucuronide, but importantly, a small proportion is transformed into morphine. A positive test for morphine can therefore sometimes occur due to codeine use (but not the other way around). A warning: most tests underestimate the amount of codeine in urine, as the metabolite codeine-6 glucuronide is hard to "bust" into codeine, which can be detected. It is important to know the relative amounts of morphine and codeine in a urine sample as the ratios affect correct interpretation as to what may or may not have been ingested.
Diazepam is broken down into another active metabolite, oxazepam. This can occur via two intermediaries, nordiazepam and temazepam. Most of the common sedatives and related drugs such as clobazam will show up as benzos on the initial immunoassay. However, specific confirmatory testing must be done when clobazam is used in therapeutic trials to test against ‘street’ benzos.
Stimulants were then covered including the new definition of ice in an age of global warming (ice-bergs and all!). Amphetamine was first synthesised by the Germans in 1887. It was heavily marketed in the US in the 1930s as ‘Benzedrine’. Methylamphetamine is easier to manufacture, especially if one has the base product pseudoephedrine. We were then told that the latest ‘craze’ for stimulants is purely based on stronger, highly purified drug being available in the form of ‘crystal meth’ or ‘ice’. Methylamphetamine powder is a salt, "crystal" a highly purified salt, and "base" is an oil. Urine testing cannot distinguish between them as these are the same drug. While Dr Lewis’ lab has found 2005 was the year with highest mean amphetamine levels, in 2006 the maximum levels found each week continued to climb to being 5 fold the 2003 levels. While these are dramatic findings, it is hard to know their significance overall except to imply that some users are taking very large amounts of methylamphetamine, viz, “ice”.
Cannabis has many metabolites which are detected on screening, and confirmed with carboxy –THC on GCMS. It is very lipophilic, and gets stored in the fat cells of the body. Cannabinoid urine tests may be negative within a few hours of a single smoke; daily use may take many days, and heavy use a month or more. If a high level is found then it is easy to know that there is continuous use. Carboxy-THC: creatinine ratios can indicate increasing or decreasing use (see case vignettes below).
Then there was a discussion about laboratory ‘cut-offs’ which are essential for legal purposes, but less meaningful for clinical purposes, except to reduce the numbers of false positives. Cut-offs are also necessarily somewhat arbitrary, like the drink driving limits - and can vary from place to place or from time to time. Currently 50ng/ml is used for immunoassays of cannabinoids, and 15 ng/ml for the specific GCMS for carboxy-THC (plus or minus a figure for lab uncertainty; this means an actual cut off of around 18-19 ng/ml). Dr Lewis believes there is a case for higher cut-offs to be used for cannabinoids, to identify substantial cannabis use, rather than low level or more importantly residual drug from previous heavy use.
Some case vignettes in the second half illustrated common problems. Three patients with positive immunoassay for opiates claimed only to have taken codeine-based analgesics. One had codeine and morphine on GCMS, and this could be explained by metabolism of codeine to morphine, or other sources or morphine such as poppy seeds, morphine sulphate etc. Another had urine positive for morphine, and negative for codeine: this could occur if there was extensive metabolism of codeine to morphine (for example by cytochrome CYP2D6 ultrarapid metabolisers) and especially if the laboratory test underestimated the amount of codeine (see above). In the last case, urine was positive for morphine and monoacetyl-morphine: the latter can only come from heroin use.
In a case of roadside drug testing, a woman justified her positive salivary cannabis test by saying "I never smoke pot, but my partner smokes it all the time". Dr Lewis explained that this test does not pick up metabolites of THC, only the parent drug, and is not very sensitive, missing a large proportion of cannabis users (as reported by the European ROSITA study). Thus passive smoking could not cause a positive test. A man on methadone, who had not had a positive urine test for many years, blamed his positive urine cannabinoid test on his partner, who ‘smoked 30 cones each day’. A positive immunoassay test result is unlikely to be a result of passive inhalation. It is more likely be a false positive due to other medication, cross contamination or else laboratory error.
Dr Lewis described the benefits of using carboxy-THC:creatinine levels to help allow for variation in urine concentrations due to level of hydration. Cases were shown from the Drug Court, where declining THC:creatinine ratios were consistent with ongoing abstinence; in another case a spike in ration of THC:creatinine led to punitive action, but might have been explained by the person going to the gym, and mobilising cannabinoids stored in fat cells.
Another case from the Drug Court showed how the sequence of appearance or disappearance of diazepam metabolites (nordiazepam, oxazepam and temazepam) could be used to make inferences about recent diazepam use. In this case, as in almost every example discussed, Dr Lewis was able to give examples of exceptions, where other causes than the most obvious might account for the result. So urine tests should never be interpreted uncritically by untrained people.
In another case, a worker was suspended for producing "dilute urine" (wrongly described as a "false negative urine test") because of low creatinine urine (1.4 mmol/L), and allegedly told he would need to produce two urine tests with creatinine higher than 5 mmol/L. However, this worker's serum creatinine was low owing to lean body build, while urea, electrolytes, specific gravity, osmolality were consistent with physiological urine. THC:creatinine ratios might help adjust for hydration (some people deliberately drink lots of water to dilute their urine) but could also discriminate against people with naturally low creatinine. A urine creatinine level as low as 0.9 mmol/L is physiologically achievable. Below this suggests the likelihood, and below 0.5 mmol/L the near certainty, of external interference with the sample, usually meaning dilution after urination.
Laboratories and clinicians need to be careful with the information they give as employers may misinterpret loose terminology.
Comments by Andrew Byrne, Richard Hallinan and Judith Meldrum, from Dr Lewis’ talk and power point presentation.
22 May 2007
20 March 2007
Methadone side effects, separating fact and fiction.
Concord Dependency Seminar, Tuesday 20 March, 2007
"Methadone side effects, separating fact and fiction".
The evening began with Dr Adam Winstock's overview of a recent study of about 1000 patients on methadone and buprenorphine, suggesting high rates of side effects: sweating, sexual dysfunction, sedation and constipation. Patients wanted help with these issues but many had not discussed them with their opioid prescriber. The biggest problem regarded as a consequence of methadone / buprenorphine was dental difficulties. Surprisingly there were few differences in side effect profiles between either medication, and other than sedation there was no clear dose relationship with any side effects, nor a relationship with the duration of treatment.
Since side effects are problematic and can be reduced with appropriate treatment in some cases, and since many patients’ attributions are incorrect, managing side effects should be more frequently addressed in consultations according to Dr Winstock. Fewer side effects may lead to better retention and improved health generally in the drug dependent population.
Dr Richard Hallinan then looked at hormonal, sexual and dental problems in methadone maintenance treatment (MMT), starting with some quite early studies. In 1970, over 200 MMT patients retrospectively compared their current complaints with their time before MMT (Bloom and Butcher 1970). 80% on MMT (versus 3% before MMT) complained of weight gain; 40% (versus 15%) of increased use of alcohol; 70% (versus 58%) constipation; 32% (versus 12%) numbness of hands and feet; and 60% (versus 49%) had difficulty with ejaculation.
However, a prospective study of 180 men and women before and during MMT (Garbutt and Goldstein, 1972) showed improvements in most physical symptoms during MMT, including aches and pains in muscles, bones and joints, craving, sweating, anorexia and nausea, headaches and insomnia, with little change in constipation, impotence and climax problems.
What are addicts like before MMT? Wilczek et al (2002) reported test results on over 100 men and women before they started MMT, finding low haemoglobin (24%), elevated CRP (25%), low testosterone levels (in males, 63%). Imaging methods revealed hepatomegaly in 28% and splenomegaly in 27% with liver steatosis in 15%.
Does methadone cause obesity? Szpanowska-Wohn et al (2004) reported statistically significant growth of body weight, in 48 men and women during 9 months of MMT, with fewer underweight and more overweight or obese people. Given the prevalence of overweight and obesity in the general community, it is however not clear whether this is a return to "societal norms" or a direct causal effect.
Do people on MMT have sexual dysfunction? Compared with 41 normal controls, Teusch et al 1995 found 37 MMT men and women differed significantly in sexual interest, emotional arousal, physiological arousal, performance and orgasm satisfaction. However as noted above, they may be better or little different from their time on heroin.
A number of studies have shown that plasma testosterone is lower in male heroin addicts than controls. Many studies in animals and humans have shown that opioids suppress testosterone, acting at the level of the hypothalamus to reduce secretion of gonadotrophins: "hypogonadotrophic hypogonadism". Amenorrhoea is common in women using heroin, and menstrual cycles tend to normalise during MMT (Schmittner et al 2005).
However, studies of men on prescribed opioids have given contradictory results. Only 10% of 92 MMT men reported by Brown et al (2005) had low testosterone, but low mean testosterone was reported in 54 men taking oral sustained-action opioids for chronic pain (Daniell, 2002); and also in 37 men on methadone maintenance (Bliesener et al 1995) while the mean testosterone level of buprenorphine-treated patients did not differ from that of healthy controls. Bliesener et al suggest buprenorphine might be preferred over methadone for this reason. Daniell has called for androgen replacement for men taking opioids who have low testosterone, citing low energy, muscle weakness, sexual dysfunction and higher risk of osteoporosis.
Wilczek and Stepan (2003) reported on bone mineral density (BMD) and metabolism before and during MMT, finding that heroin addicts had low average BMD; after one year of MMT, BMD remained unchanged, although osteo-resorption and -formation markers normalised. Recently Kim et al 2006 have reported osteoporosis in 35% and osteopenia in 48% of 92 patients in MMT, with male gender, lower weight and heavy alcohol as risk factors. However this study group may have been at higher risk (eg high rates of HIV medication and the possibility of self-selection in the study recruitment).
On the available evidence, screening for osteoporosis probably should be targeted, rather than universal, in men and women on MMT: heavy alcohol smoking, poor diet, history of low stress fractures, and hypogonadism are risk factors to consider.
Two studies have reported reduced sperm quality in men on MMT and in heroin addicts: Cicero et al in 1975, but in these studies controls were lacking or poorly matched and alcohol may have been a confounder.
Several studies have shown high caries rate and severe periodontal disease in heroin addicts, and excessive intake of food with a high sugar content is common (Scheutz 1995, Zador et al 1996). Although drug addicts often only realized how poor their dental health had become during periods of abstinence (Scheutz, 1995), caries increments were higher among people on methadone maintenance than current heroin abusers, but not statistically significant (Scheutz, 1984).
Opioids, like antidepressants, anti-cholinergics and HIV medications, may cause xerostomia (dry mouth) and this is considered a risk factor for dental disease (see Concord Seminar 20 May 2003. Dental problems in addiction treatment subjects: does methadone rot teeth? Can we prevent dental decay? Dr Peter Foltyn).
Gingivitis is a reversible inflammatory disease of the periodontal tissues, and periodontitis, in addition, involves destruction of the supporting structures of teeth. Smokers are more susceptible to periodontal diseases, and alcoholics compared with 100 non-addicts exhibited intensive dental caries (Gerlach and Wolters 1977). Poor periodontal health with reduced salivary flow has also been reported in people with chronic HCV, and use of cannabinoids has been associated with increased xerostomia (dry mouth) and severe gingivitis (Fazzi et al 1999).
Despite all of these potential confounders to a relationship between opioids (prescribed or illicit) and dental and peridontal disease, a detailed epidemiological study with control for confounders is still lacking. In the meantime, it is reasonable to give the following oral health advice to people on opioid replacement treatment:
"Give up smoking. Brush your gums, not just the teeth. Make sure your diet is balanced and avoid excessive high sugar foods. If dry mouth is a problem, try oral lubricants (like 'Oral Balance') especially at night, and dry mouth toothpaste and mouthwash (eg 'Biotene' toothpaste + mouthwash). Avoid alcohol-based mouthwashes, which dry the mouth."
Dr Andrew Byrne then spoke on constipation, sweating and prolonged QT in methadone maintenance.
Constipation and sweating are common in patients on methadone, probably more commonly at high doses but also at quite low doses such as 30mg daily. The symptoms are usually of a minor nature and require no more than sympathy, explanation and reassurance. Occasionally these may be severe enough to need further attention. If they are ignored, some patients may even drop out of treatment.
Constipation can mean different things to different people so clarification is needed about frequency, consistency, bleeding, haemorrhoids, bloating, diet, etc. There is no single approach but we should always address exercise, fluids, diet and consider laxatives or suppositories/enemas if other measures fail. Specialists advise avoiding bowel irritants such as senna and related compounds since these can cause colitis in long-term use. Luminal agents such as Magnesium sulphate, mannitol, lactulose, etc can be used while there are combination products which some patients find acceptable (Movacol, Microlax, Coloxyl with danthron).
Sweating likewise can occasionally be so troublesome that patients need help. There may be saturated clothing in the daytime while at night, sheets and pyjamas may need changing due to excessive sweating from methadone. The precise cause is unknown: candidates include hypothalamic and autonomic mechanisms, and histamine release. There may be multiple aetiologies since some get it after the dose, others when in withdrawal and other still at unpredictable times. It may also be seasonal and can respond to reassurance and slight dose reductions.
Two medications may be worth trying. The drug loratadine (‘Claratyne’) is an over-the-counter ‘non-drowsy’ antihistamine. A stronger and more specific medication is the anticholinergic drug propantheline (‘Pro-banthine’). The latter may cause dry mouth, dizziness and other autonomic side effects so patients may wish to cut it in two (which needs a pill cutter as the tablet is not scored).
Dr Byrne then pointed out that purported methadone related cardiac conduction problems were like a Miss Marple mystery without a body. After 40 years of successful use across the world it would be unlikely that a serious side effect would suddenly be recognised. And, despite the initial report in 2002 by Krantz and colleagues of 17 non-fatal cases on high doses (average 400mg daily), there has still been no series of cases reported in regular maintenance patients.
Prolonged QT and ventricular fibrillation remain rare complications of many common medications, often also involving serious concurrent metabolic and structural disturbances. Krantz, who has written about the possible dangers of prolonged QT interval in Lancet, does not recommend ECG in new MMT patients. The NSW Health Department has advised performing a cardiac assessment including electrocardiogram for patients who are being considered for high dose methadone (>200mg daily). This would seem to be a reasonable precaution.
In the second half, several case "vignettes" were presented, including three cases of low testosterone in opioid-treated men.
Gert, 41 yo, on MMT with a current dose 70 mg, was found on screening to have low total testosterone: 5.5 nmol/L; his testosterone dropped to 3.7 nmol/L despite methadone dose reductions to 55mg. Luteinising hormone (LH) was low. His BMI was 29. Abdominal ultrasound showed fatty liver. His dual energy X-ray densitometry (DEXA) scan showed osteoporosis, with lumbar T-score -2.6.
He was seen by an endocrinologist, and on questioning admitted to low energy, low libido, increasing erectile dysfunction, hot flushes, weight gain in last 12 months. Prostate examination and specific antigen (PSA) were normal. He was started on androgen replacement with "Androderm" patches, with resolution of his hot flushes, low energy, low libido, and erectile dysfunction. However patches caused skin irritation, and he much preferred "Sustanon" injections, and later testosterone transdermal gel. At follow up DEXA a year later, lumbar T-score had improved to -1.9.
This brief presentation was filled in after questions from the audience: Gert's testicular volumes were normal. Liver function tests, full blood count, thyroid function tests and prolactin were normal. Visual fields were normal (cerebral CT was not done). The main reason for treatment in this case was osteoporosis (not sexual dysfunction, which the patient had not actually complained about). Testosterone assays were performed in the morning, as recommended.
We were reminded of the Australian Endocrine Society for androgen replacement treatment: for persistent hypogonadism (at least two morning testosterone levels below 8.0 nmol/L); if there are symptoms of low energy, mood, muscle strength, sexual dysfunction, especially if there is osteopenia, osteoporosis. Prefer testosterone and its esters to synthetic androgens, check the prostate and PSA in men >40yo. Beware the marked placebo effect that often occurs with androgen replacement, which may lead to subsequent disappointment.
It was pointed out that haemochromatosis should have been considered in the differential diagnosis (the endocrinologist in this case notes that haemochromatosis and pituitary tumour are the 2 classic exclusions for the diagnosis of hypogonadotrophic hypogonadism. In this case no other clinical features of haemochromatosis were present, but hypogonadism caused by iron deposits in the pituitary can present in isolation from other features of haemochromatosis. Iron studies were normal in this patient).
The second case was Ben, a 31 year old labourer from regional NSW, who had been on buprenorphine maintenance the last 2 years, after previous MMT. His alcohol use was very heavy from his late teens, he injected amphetamines from age 21 and heroin from age 23. He was HIV, HBV and HCV seronegative and liver function tests were normal.
With his buprenorphine dose 8-12mg daily, he was prescribed sildenafil as he had formed a new relationship and complained of erectile problems. His total testosterone was low at 7.3 nmol/L with low LH, and he was referred to sexual health physician. Penile Doppler was normal, and there was a poor erectile response to a prostaglandin challenge. Follow up testosterone was 8.7 nmol/L. He was advised that his erectile dysfunction was psychogenic.
Ben continued to have erectile dysfunction, and resented needing PDE-5 inhibitors. He reduced his buprenorphine dose precipitously, then returned needing dose supplements. Continuing reductions were accompanied by a rise in testosterone in to the high normal range, but erectile dysfunction remained intermittently a problem.
A year later his wife blamed buprenorphine for their failure to conceive, insisting he come off treatment, despite by now normal testosterone. Ben was was worried about his sperm count. After counseling, they attended a fertility clinic. Ben's sperm count was normal, his wife's ovarian cyst was removed, and ‘they’ become pregnant 8 weeks later.
After reducing his dose to 0.4 mg, Ben came off buprenorphine with protracted symptoms requiring mirtazepine, clonidine, and eventually temazepam. He was off BMT for the birth of his son, but relapsed into heroin use 8 months later.
This case illustrated the risk that sexual dysfunction may destabilise opioid replacement treatment; that buprenorphine can be associated with low testosterone and sexual dysfunction; that androgen replacement is not necessarily needed whenever testosterone is low.
Bill was a 56 yo man, on MMT continuously since 1991, his current dose 65mg. He had injected heroin since age 22. His current alcohol use was 70-140g/day, and he smoked 10 cigarettes/day. He had chronic back pain after a minor injury in 1999, and fractured his right humerus after slipping in a puddle 2002. He was admitted to hospital with (?aspiration) pneumonia in 2000.
Bill had Dupuytrens contractures, spiders, palmar erythema. His blood tests showed elevated GGT and AST, normal ALT, low platelets (130), normal haemoglobin but macrocytosis. He was HCV seropositive and repeatedly HCV-RNA negative.
His morning total testosterone was 10.0 nmol/L and 7.2 nmol/L on two occasions (normal 12-36). With his worsening kyphosis, X rays showed wedge fractures of the thoracic spine, and loss of height in lumbar spine. DEXA showed osteoporosis (T score -4.1 spine and -3.0 at hip). Serum folate was low at 3.7 (>7.0).
Bill was referred to an endocrinologist, who noted his low BMI (18.8). Coeliac screen, and 25-OH Vitamin D were normal. A repeat total testosterone was 12.1 nmol/L.
After dental review, bisphosphonate was prescribed, with calcium supplements and folate.
Among the ‘messages’ of this case: the likely importance of alcohol, smoking and dietary factors in the genesis of osteoporosis in this man; the need to check other causes of macrocytosis in an alcoholic; and again, the need not to rush in with androgen replacement.
Finally there was a case vignette, to put things in perspective: “I've been on a hundred mils of methadone a day for 25 years and I'm as fit as a fiddle! Most of the people who I started using with are long since dead. I consider methadone has kept me alive, and is the best tonic ever invented.”
Summary written by R. Hallinan, A. Winstock and A Byrne.
"Methadone side effects, separating fact and fiction".
The evening began with Dr Adam Winstock's overview of a recent study of about 1000 patients on methadone and buprenorphine, suggesting high rates of side effects: sweating, sexual dysfunction, sedation and constipation. Patients wanted help with these issues but many had not discussed them with their opioid prescriber. The biggest problem regarded as a consequence of methadone / buprenorphine was dental difficulties. Surprisingly there were few differences in side effect profiles between either medication, and other than sedation there was no clear dose relationship with any side effects, nor a relationship with the duration of treatment.
Since side effects are problematic and can be reduced with appropriate treatment in some cases, and since many patients’ attributions are incorrect, managing side effects should be more frequently addressed in consultations according to Dr Winstock. Fewer side effects may lead to better retention and improved health generally in the drug dependent population.
Dr Richard Hallinan then looked at hormonal, sexual and dental problems in methadone maintenance treatment (MMT), starting with some quite early studies. In 1970, over 200 MMT patients retrospectively compared their current complaints with their time before MMT (Bloom and Butcher 1970). 80% on MMT (versus 3% before MMT) complained of weight gain; 40% (versus 15%) of increased use of alcohol; 70% (versus 58%) constipation; 32% (versus 12%) numbness of hands and feet; and 60% (versus 49%) had difficulty with ejaculation.
However, a prospective study of 180 men and women before and during MMT (Garbutt and Goldstein, 1972) showed improvements in most physical symptoms during MMT, including aches and pains in muscles, bones and joints, craving, sweating, anorexia and nausea, headaches and insomnia, with little change in constipation, impotence and climax problems.
What are addicts like before MMT? Wilczek et al (2002) reported test results on over 100 men and women before they started MMT, finding low haemoglobin (24%), elevated CRP (25%), low testosterone levels (in males, 63%). Imaging methods revealed hepatomegaly in 28% and splenomegaly in 27% with liver steatosis in 15%.
Does methadone cause obesity? Szpanowska-Wohn et al (2004) reported statistically significant growth of body weight, in 48 men and women during 9 months of MMT, with fewer underweight and more overweight or obese people. Given the prevalence of overweight and obesity in the general community, it is however not clear whether this is a return to "societal norms" or a direct causal effect.
Do people on MMT have sexual dysfunction? Compared with 41 normal controls, Teusch et al 1995 found 37 MMT men and women differed significantly in sexual interest, emotional arousal, physiological arousal, performance and orgasm satisfaction. However as noted above, they may be better or little different from their time on heroin.
A number of studies have shown that plasma testosterone is lower in male heroin addicts than controls. Many studies in animals and humans have shown that opioids suppress testosterone, acting at the level of the hypothalamus to reduce secretion of gonadotrophins: "hypogonadotrophic hypogonadism". Amenorrhoea is common in women using heroin, and menstrual cycles tend to normalise during MMT (Schmittner et al 2005).
However, studies of men on prescribed opioids have given contradictory results. Only 10% of 92 MMT men reported by Brown et al (2005) had low testosterone, but low mean testosterone was reported in 54 men taking oral sustained-action opioids for chronic pain (Daniell, 2002); and also in 37 men on methadone maintenance (Bliesener et al 1995) while the mean testosterone level of buprenorphine-treated patients did not differ from that of healthy controls. Bliesener et al suggest buprenorphine might be preferred over methadone for this reason. Daniell has called for androgen replacement for men taking opioids who have low testosterone, citing low energy, muscle weakness, sexual dysfunction and higher risk of osteoporosis.
Wilczek and Stepan (2003) reported on bone mineral density (BMD) and metabolism before and during MMT, finding that heroin addicts had low average BMD; after one year of MMT, BMD remained unchanged, although osteo-resorption and -formation markers normalised. Recently Kim et al 2006 have reported osteoporosis in 35% and osteopenia in 48% of 92 patients in MMT, with male gender, lower weight and heavy alcohol as risk factors. However this study group may have been at higher risk (eg high rates of HIV medication and the possibility of self-selection in the study recruitment).
On the available evidence, screening for osteoporosis probably should be targeted, rather than universal, in men and women on MMT: heavy alcohol smoking, poor diet, history of low stress fractures, and hypogonadism are risk factors to consider.
Two studies have reported reduced sperm quality in men on MMT and in heroin addicts: Cicero et al in 1975, but in these studies controls were lacking or poorly matched and alcohol may have been a confounder.
Several studies have shown high caries rate and severe periodontal disease in heroin addicts, and excessive intake of food with a high sugar content is common (Scheutz 1995, Zador et al 1996). Although drug addicts often only realized how poor their dental health had become during periods of abstinence (Scheutz, 1995), caries increments were higher among people on methadone maintenance than current heroin abusers, but not statistically significant (Scheutz, 1984).
Opioids, like antidepressants, anti-cholinergics and HIV medications, may cause xerostomia (dry mouth) and this is considered a risk factor for dental disease (see Concord Seminar 20 May 2003. Dental problems in addiction treatment subjects: does methadone rot teeth? Can we prevent dental decay? Dr Peter Foltyn).
Gingivitis is a reversible inflammatory disease of the periodontal tissues, and periodontitis, in addition, involves destruction of the supporting structures of teeth. Smokers are more susceptible to periodontal diseases, and alcoholics compared with 100 non-addicts exhibited intensive dental caries (Gerlach and Wolters 1977). Poor periodontal health with reduced salivary flow has also been reported in people with chronic HCV, and use of cannabinoids has been associated with increased xerostomia (dry mouth) and severe gingivitis (Fazzi et al 1999).
Despite all of these potential confounders to a relationship between opioids (prescribed or illicit) and dental and peridontal disease, a detailed epidemiological study with control for confounders is still lacking. In the meantime, it is reasonable to give the following oral health advice to people on opioid replacement treatment:
"Give up smoking. Brush your gums, not just the teeth. Make sure your diet is balanced and avoid excessive high sugar foods. If dry mouth is a problem, try oral lubricants (like 'Oral Balance') especially at night, and dry mouth toothpaste and mouthwash (eg 'Biotene' toothpaste + mouthwash). Avoid alcohol-based mouthwashes, which dry the mouth."
Dr Andrew Byrne then spoke on constipation, sweating and prolonged QT in methadone maintenance.
Constipation and sweating are common in patients on methadone, probably more commonly at high doses but also at quite low doses such as 30mg daily. The symptoms are usually of a minor nature and require no more than sympathy, explanation and reassurance. Occasionally these may be severe enough to need further attention. If they are ignored, some patients may even drop out of treatment.
Constipation can mean different things to different people so clarification is needed about frequency, consistency, bleeding, haemorrhoids, bloating, diet, etc. There is no single approach but we should always address exercise, fluids, diet and consider laxatives or suppositories/enemas if other measures fail. Specialists advise avoiding bowel irritants such as senna and related compounds since these can cause colitis in long-term use. Luminal agents such as Magnesium sulphate, mannitol, lactulose, etc can be used while there are combination products which some patients find acceptable (Movacol, Microlax, Coloxyl with danthron).
Sweating likewise can occasionally be so troublesome that patients need help. There may be saturated clothing in the daytime while at night, sheets and pyjamas may need changing due to excessive sweating from methadone. The precise cause is unknown: candidates include hypothalamic and autonomic mechanisms, and histamine release. There may be multiple aetiologies since some get it after the dose, others when in withdrawal and other still at unpredictable times. It may also be seasonal and can respond to reassurance and slight dose reductions.
Two medications may be worth trying. The drug loratadine (‘Claratyne’) is an over-the-counter ‘non-drowsy’ antihistamine. A stronger and more specific medication is the anticholinergic drug propantheline (‘Pro-banthine’). The latter may cause dry mouth, dizziness and other autonomic side effects so patients may wish to cut it in two (which needs a pill cutter as the tablet is not scored).
Dr Byrne then pointed out that purported methadone related cardiac conduction problems were like a Miss Marple mystery without a body. After 40 years of successful use across the world it would be unlikely that a serious side effect would suddenly be recognised. And, despite the initial report in 2002 by Krantz and colleagues of 17 non-fatal cases on high doses (average 400mg daily), there has still been no series of cases reported in regular maintenance patients.
Prolonged QT and ventricular fibrillation remain rare complications of many common medications, often also involving serious concurrent metabolic and structural disturbances. Krantz, who has written about the possible dangers of prolonged QT interval in Lancet, does not recommend ECG in new MMT patients. The NSW Health Department has advised performing a cardiac assessment including electrocardiogram for patients who are being considered for high dose methadone (>200mg daily). This would seem to be a reasonable precaution.
In the second half, several case "vignettes" were presented, including three cases of low testosterone in opioid-treated men.
Gert, 41 yo, on MMT with a current dose 70 mg, was found on screening to have low total testosterone: 5.5 nmol/L; his testosterone dropped to 3.7 nmol/L despite methadone dose reductions to 55mg. Luteinising hormone (LH) was low. His BMI was 29. Abdominal ultrasound showed fatty liver. His dual energy X-ray densitometry (DEXA) scan showed osteoporosis, with lumbar T-score -2.6.
He was seen by an endocrinologist, and on questioning admitted to low energy, low libido, increasing erectile dysfunction, hot flushes, weight gain in last 12 months. Prostate examination and specific antigen (PSA) were normal. He was started on androgen replacement with "Androderm" patches, with resolution of his hot flushes, low energy, low libido, and erectile dysfunction. However patches caused skin irritation, and he much preferred "Sustanon" injections, and later testosterone transdermal gel. At follow up DEXA a year later, lumbar T-score had improved to -1.9.
This brief presentation was filled in after questions from the audience: Gert's testicular volumes were normal. Liver function tests, full blood count, thyroid function tests and prolactin were normal. Visual fields were normal (cerebral CT was not done). The main reason for treatment in this case was osteoporosis (not sexual dysfunction, which the patient had not actually complained about). Testosterone assays were performed in the morning, as recommended.
We were reminded of the Australian Endocrine Society for androgen replacement treatment: for persistent hypogonadism (at least two morning testosterone levels below 8.0 nmol/L); if there are symptoms of low energy, mood, muscle strength, sexual dysfunction, especially if there is osteopenia, osteoporosis. Prefer testosterone and its esters to synthetic androgens, check the prostate and PSA in men >40yo. Beware the marked placebo effect that often occurs with androgen replacement, which may lead to subsequent disappointment.
It was pointed out that haemochromatosis should have been considered in the differential diagnosis (the endocrinologist in this case notes that haemochromatosis and pituitary tumour are the 2 classic exclusions for the diagnosis of hypogonadotrophic hypogonadism. In this case no other clinical features of haemochromatosis were present, but hypogonadism caused by iron deposits in the pituitary can present in isolation from other features of haemochromatosis. Iron studies were normal in this patient).
The second case was Ben, a 31 year old labourer from regional NSW, who had been on buprenorphine maintenance the last 2 years, after previous MMT. His alcohol use was very heavy from his late teens, he injected amphetamines from age 21 and heroin from age 23. He was HIV, HBV and HCV seronegative and liver function tests were normal.
With his buprenorphine dose 8-12mg daily, he was prescribed sildenafil as he had formed a new relationship and complained of erectile problems. His total testosterone was low at 7.3 nmol/L with low LH, and he was referred to sexual health physician. Penile Doppler was normal, and there was a poor erectile response to a prostaglandin challenge. Follow up testosterone was 8.7 nmol/L. He was advised that his erectile dysfunction was psychogenic.
Ben continued to have erectile dysfunction, and resented needing PDE-5 inhibitors. He reduced his buprenorphine dose precipitously, then returned needing dose supplements. Continuing reductions were accompanied by a rise in testosterone in to the high normal range, but erectile dysfunction remained intermittently a problem.
A year later his wife blamed buprenorphine for their failure to conceive, insisting he come off treatment, despite by now normal testosterone. Ben was was worried about his sperm count. After counseling, they attended a fertility clinic. Ben's sperm count was normal, his wife's ovarian cyst was removed, and ‘they’ become pregnant 8 weeks later.
After reducing his dose to 0.4 mg, Ben came off buprenorphine with protracted symptoms requiring mirtazepine, clonidine, and eventually temazepam. He was off BMT for the birth of his son, but relapsed into heroin use 8 months later.
This case illustrated the risk that sexual dysfunction may destabilise opioid replacement treatment; that buprenorphine can be associated with low testosterone and sexual dysfunction; that androgen replacement is not necessarily needed whenever testosterone is low.
Bill was a 56 yo man, on MMT continuously since 1991, his current dose 65mg. He had injected heroin since age 22. His current alcohol use was 70-140g/day, and he smoked 10 cigarettes/day. He had chronic back pain after a minor injury in 1999, and fractured his right humerus after slipping in a puddle 2002. He was admitted to hospital with (?aspiration) pneumonia in 2000.
Bill had Dupuytrens contractures, spiders, palmar erythema. His blood tests showed elevated GGT and AST, normal ALT, low platelets (130), normal haemoglobin but macrocytosis. He was HCV seropositive and repeatedly HCV-RNA negative.
His morning total testosterone was 10.0 nmol/L and 7.2 nmol/L on two occasions (normal 12-36). With his worsening kyphosis, X rays showed wedge fractures of the thoracic spine, and loss of height in lumbar spine. DEXA showed osteoporosis (T score -4.1 spine and -3.0 at hip). Serum folate was low at 3.7 (>7.0).
Bill was referred to an endocrinologist, who noted his low BMI (18.8). Coeliac screen, and 25-OH Vitamin D were normal. A repeat total testosterone was 12.1 nmol/L.
After dental review, bisphosphonate was prescribed, with calcium supplements and folate.
Among the ‘messages’ of this case: the likely importance of alcohol, smoking and dietary factors in the genesis of osteoporosis in this man; the need to check other causes of macrocytosis in an alcoholic; and again, the need not to rush in with androgen replacement.
Finally there was a case vignette, to put things in perspective: “I've been on a hundred mils of methadone a day for 25 years and I'm as fit as a fiddle! Most of the people who I started using with are long since dead. I consider methadone has kept me alive, and is the best tonic ever invented.”
Summary written by R. Hallinan, A. Winstock and A Byrne.
31 January 2007
Amphetamine/Stimulant Use: Presentations, complications, interventions.
Concord Seminar Tuesday 30 January 2007
Amphetamine/Stimulant Use: Presentations, complications, interventions.
Speakers: Dr Alex Wodak, Director of the Alcohol and Drug Service, and Ms Tarra Adam, Stimulant Treatment Program, Clinical Program Manager, St Vincent’s Hospital, Darlinghurst. Chaired by Dr Bob Batey.
Dear Colleagues,
Dr Wodak gave an overview of increasing amphetamine use around the world. In 2002, of 91 countries, 56 showed increasing "abuse" of amphetamines, and 11 showed a decrease. There was an increase in amphetamine labs in the years from 1998 to 2004 of 300 to 18,000, with production of Amphetamine Type Substances (ATS) rising from 312 tons to 480 (UNODCCP Global Illicit Drug Trends 2002). Among 15-64 year olds in 2006 there was a prevalence of ATS use in Asia of 0.6%, Oceania of 3%, and Global 0.6% (UNDCP 2006 World Drug Report).
Australian Institute of Health and Welfare statistics show an increase in admissions for amphetamine-related psychosis, from approximately 1000 in 1999/2000 to approximately 1600 in 2003/2004. There has probably been a further increase since then, however the increases have been patchy across the country, with increases in NSW and Victoria being less than other states (a large increase in the year 1999 can be attributed to the change from ICD 9 to ICD 10 definitions).
Recently there has been a trend away from plant based substances to chemical based drugs due to efforts to avoid both the vagaries of weather, and improved surveillance by air and satellite.
To get an idea of the size of the problem in economic terms Dr Wodak pointed out that the size of the illicit "drug industry" in the UK was about the same as British Airways.
Regarding the cost effectiveness of treatment, there have not been any studies specifically looking at amphetamines but it is more cost effective to spend money on cocaine drug treatment than on drug law enforcement (Rydell, Everingham. Controlling Cocaine: Supply Versus Demand Programs, RAND, 1994.) Because of similarities to cocaine, these conclusions may be also relevant to amphetamines.
In the words of the economist Milton Friedman: "So long as large sums of money are involved - and they are bound to be if drugs are illegal - it is literally hopeless to expect to end the traffic or even to reduce seriously its scope. In drugs, as in other areas, persuasion and example are likely to be far more effective than the use of force to shape others in our image."
Dr Wodak described typical presentations of amphetamine use: a psychosis that looks like schizophrenia; severe, even suicidal, depression; aggressive behaviour; strokes, hypertension, and arrhythmias; possibly risky sex including HIV risk; infections from injecting drug use including HCV, septicaemia, bacterial endocarditis; and general "social catastrophes" - financial problems, lost jobs and broken relationships, and gambling problems.
No specific regimen has been found to be better or worse than any other for withdrawal management, as amphetamine withdrawal is not well understood.
Cochrane reviews have found evidence about the treatment for amphetamine psychosis is limited: medications of interest are conventional antipsychotics, newer antipsychotics and benzodiazepines. An injection of "anti-psychotic drugs can help relieve the symptoms of amphetamine psychosis within an hour, but there is not enough evidence to show what can help after that".
Among psychosocial interventions for amphetamine dependence, motivational interviewing and cognitive behavioural therapy show promise. Most in the audience had not used the excellent recommended handbook by Baker, Kay-Lambkin, Lee, Claire and Jenner. “A Brief Cognitive Behavioural Intervention for Regular Amphetamine Users” Department of Health and Ageing 2003 - downloadable from the web: http://www.health.gov.au/internet/wcms/publishing.nsf/Content/health-pubhlth-publicat-document-cognitive_intervention-cnt.htm/$FILE/cognitive_intervention.pdf
Among non-agonist pharmacological treatments for amphetamine dependence, 30-40 different drugs have been evaluated but none really found to be helpful (see Cochrane Review).
Setting the context for agonist pharmacological treatments, Dr Wodak gave the following overview: some amphetamine, especially methamphetamine, users become very chaotic, very volatile, and some become violent. As they may develop paranoia or psychosis, so engaging patients often takes longer, and may be much harder than with other substance dependent patients. They need access to prompt, effective mental health support, and most respond very positively to psychosocial interventions. However a few people with severe intractable use may need Amphetamine Substitution Treatment (AST) in combination with psychosocial interventions.
We were pointed to two reviews of the numerous studies of Amphetamine Substitution Treatment (dating from Griffith Edward’s first study in the 1960s, which gave negative results).
· Shearer J, Sherman J, Wodak A, van Beek I. Substitution therapy for amphetamine users. Drug and Alcohol Review 2002; 21 (2), 179-185.
· Grabowski J, Shearer J, Merrill J, Negus S. Agonist-like replacement pharmacotherapy for stimulant abuse and dependence. Addictive Behaviors. 29 (2004); 1439-1464.
These reviews show that, comparable to the situation for methadone in the 1970s, there is reasonable evidence for the effectiveness and safety of AST. It may be not needed for as high a percentage, nor as long, as for heroin dependent people who need methadone.
Dr Wodak reminded us of the principles of drug substitution treatment:
1. to replace: a short acting drug with a longer action one; an illegal drug with a legal drug; an injectable drug with an oral drug; and
2. to stabilise, counsel, and then where ever possible wean off, as in nicotine replacement, and opioid substitution treatment.
The NSW Department of Health established Stimulant Treatment Programmes in November 2006 at St Vincent’s Hospital, Darlinghurst and in the Hunter New England region. These programmes offer psychosocial interventions but for severe and refractory cases which meet strict criteria, trials are using immediate release dexamphetamine, as slow release amphetamine (which would be preferable) is not yet licensed for use in Australia. There will be daily supervised dosing of 60mg maximum, only for people with severe intractable problems, with small numbers of about 30 per year in each centre. The programmes are being independently evaluated.
The selection criteria are very strict, as Dr Wodak believes it is wiser to start such a treatment with strict limits and later liberalise it if appropriate, rather than "let the genie out of the bottle" too soon.
The power of substitution treatment has been shown in Zurich, where there has been saturation treatment with methadone and other opioids (including prescribed heroin), accompanied by a marked decrease in heroin use, drug overdose, crime and heroin seizures by police, and an 82% reduction in new heroin users from 850 in 1990 to only 150 in 2002. (Nordt, Stohler. Lancet 2006 367 1830-34).
Another benefit may be if ATS acts like a carrot, getting people with problems to ask for help. A number of people on the waiting list for ATS at St Vincent’s Hospital have improved just with psychosocial interventions while being considered for pharmacotherapy.
Tarra Adam then spoke on her work with amphetamine users at Sydney’s St Vincent’s Hospital. She sees those that present at the hospital with problems related to amphetamine use, or who refer themselves.
Some present with aggression or violence which is out of character and worries them. Many have learnt to manage their use reasonably well, before seeking any treatment.
There is a perception that Alcohol and Drug Services are not for them, and historically these services may have had little to offer. ATS users are often suspicious of the service and whether the service can meet their needs, and may appear to be testing out the therapists, having a strong sense of what they want. Often they wish to be seen in a different area or using a separate entrance, because they are "not like the others".
Amphetamine users do tend to show a different profile, being less impoverished and more educated, motivated but hard to engage, often successful at work with a wide range of social contacts, and in better social circumstances than heroin users. Most are daily users, some injecting 3 times a day, some up to 9 times. The majority of people seen at the St Vincent’s Hospital Stimulant Treatment Program are smoking "crystal". Not many switch between amphetamines and cocaine.
A range of therapies is offered, including Motivational Interviewing, Cognitive Behavioural Therapy, and people may be referred to a “SMART Recovery” group. However CBT may be just too difficult for a person who is chaotic or paranoid, and often experience cognitive impairment during periods of use or whilst in withdrawal. In the early stages of treatment, some people find it difficult to concentrate and connect with how their thoughts and feelings influence their behaviour. In addition, talking about triggers and motivations to change with stimulant users has in our experience, increased people’s craving for the drug and can contribute to ongoing use and/ or relapse. Therefore we concentrate on addressing the wider impact of stimulant use on their sense of self, the impact of use on their relationships, rather than concentrating on the drug use itself.
Therefore, other approaches may be needed, with the aim of trying to engage the person.
Narrative Therapy is an example: here the emphasis is centred on people as the experts in their own lives. It views problems as separate from the person and holds that people come with many skills, beliefs, values and abilities that will assist them to reduce the influence of problems such as stimulants in their lives. People often present to therapy with a problem saturated story that dominates beliefs about themselves and influences the choices they make. Narrative conversations seek out the alternative/ preferred stories –stories that are identified by the person about how they would like to live their lives, what it would mean to them to make these changes and supports them to perform this meaning. The therapist seeks out examples of such stories in their lives which support people to break from the influence of the problems they are facing and create new possibilities for their future by increasing awareness of their skills, beliefs, values, and abilities to reduce the influence of stimulants in their lives. A reference for those interested to know more is "What is Narrative Therapy?" by Alice Morgan (can be ordered from the Dulwich Centre - the link for a summary of her book is: http://www.dulwichcentre.com.au/alicearticle.html)
In the second half, chaired by Dr Bob Batey, a range of case vignettes was discussed.
The first case was a woman who declared "I always shoot speed on my pension day, Doc. It is the only time I ever clean the house … but now all my veins are gone!"
Among the points raised were: possible causes of the exhaustion include following a binge, chronic hepatitis C, and depression. A question was raised about the safety of using antidepressants, including SSRIs, in people who use stimulants, including MDMA. Although this was a theoretical risk, given that these medications and drugs raise monoamine levels in synapses, the expected "epidemic of Serotonin Syndrome has not materialised", as one participant put it. It may be worth suggesting safer ways of administration, as a harm reduction measure, and may be appropriate to refer her for financial management assistance through Centrelink, which offers the Centrepay service for regular payments. It was generally agreed that she was not suitable for AST, given the intermittent nature of her use.
In the second case, a man announced "After I use crystal meth I turn into somebody else. I thought I knew how to fly and jumped off the balcony two storeys up to save using the stairs. Now I’m in plaster with two fractured heels and I can’t even get up those stairs".
Problems like this occur especially with use of other substances as well, such as benzodiazepines, and often end up in jail, or hospital. Once the person settles they may be able to look at their substance use, especially if they are laid up in hospital. An important question is how worried friends or family can help decrease the risk of harms like this: one response is that health professionals need to help "significant others" who seek help in the first instance by helping them look after themselves.
This was also true for the following case, where flatmates sought advice about a young man who had moved in recently from Darlinghurst where "it was too easy to go out every night". He regularly used "ecstasy", took Ritalin for ADD, also selegiline which he read on a web site was good for ADD. He was often up all night, constantly reorganising his room with his things strewn all over the yard. One day he declared angrily "I know you’ve been in my room snooping around. You let things slip that show that you did it. I wish I had video surveillance up there".
Tarra Adam said this was a typical presentation to the Alcohol and Drug Service at St. Vincent's Hospital, except that usually the person absolutely believes that others were doing the video surveillance.
A comment was that nothing could be taken at face value in this case: neither the ADD diagnosis, the precise substances used, nor any other psychiatric diagnosis.
In the next case, a 32 yo man, injecting ATS for 2 years, said: "I'm using ice every day and I can't pull up. Can you give me something to help me detox? Or can I go to a detox somewhere?" Even though the evidence about the amphetamine withdrawal syndrome is limited and there seems to be little benefit from medications, many "detox" facilities will admit amphetamine users. One rehab allows the person to sleep and then clean up, maintaining good hydrations being very important. As many ATS users prefer benzodiazepines to manage their withdrawal, a case could be made in community practice for dispensing a small amount of diazepam to encourage engagement with treatment in future.
The final case was a 34 yo man on MMT for 7 years, 11 years injecting, probably 10 years chronic HCV with fluctuating elevated ALT. His methadone dose was 110 mg and his total testosterone was 5.0 -7.2 mmol/L on repeated (morning) testing. He continued to inject ATS several times a week throughout MMT, saying otherwise he has no energy. He was little motivated to change his ATS use.
The reasons for this man's lack of energy could include hypogonadism (probably from opioids), chronic hepatitis C, depression, or the effect of amphetamines themselves. Among the approaches could be a trial of methadone reductions or androgen replacement (chronic viral hepatitis is not a contraindication for use of testosterone and its esters, which should be used in preference to synthetic androgens). One could offer antiviral treatment for hepatitis C, which may be a motivation to stop injecting drug use (injecting should not be a contraindication for hepatitis C treatment). a trial of antidepressants may be indicated. These strategies should probably be tried serially rather than simultaneously, to avoid diagnostic confusion in the event of an improvement in energy.
Written by Judith Meldrum and Richard Hallinan based on Dr Wodak’s talk.
http://www.redfernclinic.com/
Amphetamine/Stimulant Use: Presentations, complications, interventions.
Speakers: Dr Alex Wodak, Director of the Alcohol and Drug Service, and Ms Tarra Adam, Stimulant Treatment Program, Clinical Program Manager, St Vincent’s Hospital, Darlinghurst. Chaired by Dr Bob Batey.
Dear Colleagues,
Dr Wodak gave an overview of increasing amphetamine use around the world. In 2002, of 91 countries, 56 showed increasing "abuse" of amphetamines, and 11 showed a decrease. There was an increase in amphetamine labs in the years from 1998 to 2004 of 300 to 18,000, with production of Amphetamine Type Substances (ATS) rising from 312 tons to 480 (UNODCCP Global Illicit Drug Trends 2002). Among 15-64 year olds in 2006 there was a prevalence of ATS use in Asia of 0.6%, Oceania of 3%, and Global 0.6% (UNDCP 2006 World Drug Report).
Australian Institute of Health and Welfare statistics show an increase in admissions for amphetamine-related psychosis, from approximately 1000 in 1999/2000 to approximately 1600 in 2003/2004. There has probably been a further increase since then, however the increases have been patchy across the country, with increases in NSW and Victoria being less than other states (a large increase in the year 1999 can be attributed to the change from ICD 9 to ICD 10 definitions).
Recently there has been a trend away from plant based substances to chemical based drugs due to efforts to avoid both the vagaries of weather, and improved surveillance by air and satellite.
To get an idea of the size of the problem in economic terms Dr Wodak pointed out that the size of the illicit "drug industry" in the UK was about the same as British Airways.
Regarding the cost effectiveness of treatment, there have not been any studies specifically looking at amphetamines but it is more cost effective to spend money on cocaine drug treatment than on drug law enforcement (Rydell, Everingham. Controlling Cocaine: Supply Versus Demand Programs, RAND, 1994.) Because of similarities to cocaine, these conclusions may be also relevant to amphetamines.
In the words of the economist Milton Friedman: "So long as large sums of money are involved - and they are bound to be if drugs are illegal - it is literally hopeless to expect to end the traffic or even to reduce seriously its scope. In drugs, as in other areas, persuasion and example are likely to be far more effective than the use of force to shape others in our image."
Dr Wodak described typical presentations of amphetamine use: a psychosis that looks like schizophrenia; severe, even suicidal, depression; aggressive behaviour; strokes, hypertension, and arrhythmias; possibly risky sex including HIV risk; infections from injecting drug use including HCV, septicaemia, bacterial endocarditis; and general "social catastrophes" - financial problems, lost jobs and broken relationships, and gambling problems.
No specific regimen has been found to be better or worse than any other for withdrawal management, as amphetamine withdrawal is not well understood.
Cochrane reviews have found evidence about the treatment for amphetamine psychosis is limited: medications of interest are conventional antipsychotics, newer antipsychotics and benzodiazepines. An injection of "anti-psychotic drugs can help relieve the symptoms of amphetamine psychosis within an hour, but there is not enough evidence to show what can help after that".
Among psychosocial interventions for amphetamine dependence, motivational interviewing and cognitive behavioural therapy show promise. Most in the audience had not used the excellent recommended handbook by Baker, Kay-Lambkin, Lee, Claire and Jenner. “A Brief Cognitive Behavioural Intervention for Regular Amphetamine Users” Department of Health and Ageing 2003 - downloadable from the web: http://www.health.gov.au/internet/wcms/publishing.nsf/Content/health-pubhlth-publicat-document-cognitive_intervention-cnt.htm/$FILE/cognitive_intervention.pdf
Among non-agonist pharmacological treatments for amphetamine dependence, 30-40 different drugs have been evaluated but none really found to be helpful (see Cochrane Review).
Setting the context for agonist pharmacological treatments, Dr Wodak gave the following overview: some amphetamine, especially methamphetamine, users become very chaotic, very volatile, and some become violent. As they may develop paranoia or psychosis, so engaging patients often takes longer, and may be much harder than with other substance dependent patients. They need access to prompt, effective mental health support, and most respond very positively to psychosocial interventions. However a few people with severe intractable use may need Amphetamine Substitution Treatment (AST) in combination with psychosocial interventions.
We were pointed to two reviews of the numerous studies of Amphetamine Substitution Treatment (dating from Griffith Edward’s first study in the 1960s, which gave negative results).
· Shearer J, Sherman J, Wodak A, van Beek I. Substitution therapy for amphetamine users. Drug and Alcohol Review 2002; 21 (2), 179-185.
· Grabowski J, Shearer J, Merrill J, Negus S. Agonist-like replacement pharmacotherapy for stimulant abuse and dependence. Addictive Behaviors. 29 (2004); 1439-1464.
These reviews show that, comparable to the situation for methadone in the 1970s, there is reasonable evidence for the effectiveness and safety of AST. It may be not needed for as high a percentage, nor as long, as for heroin dependent people who need methadone.
Dr Wodak reminded us of the principles of drug substitution treatment:
1. to replace: a short acting drug with a longer action one; an illegal drug with a legal drug; an injectable drug with an oral drug; and
2. to stabilise, counsel, and then where ever possible wean off, as in nicotine replacement, and opioid substitution treatment.
The NSW Department of Health established Stimulant Treatment Programmes in November 2006 at St Vincent’s Hospital, Darlinghurst and in the Hunter New England region. These programmes offer psychosocial interventions but for severe and refractory cases which meet strict criteria, trials are using immediate release dexamphetamine, as slow release amphetamine (which would be preferable) is not yet licensed for use in Australia. There will be daily supervised dosing of 60mg maximum, only for people with severe intractable problems, with small numbers of about 30 per year in each centre. The programmes are being independently evaluated.
The selection criteria are very strict, as Dr Wodak believes it is wiser to start such a treatment with strict limits and later liberalise it if appropriate, rather than "let the genie out of the bottle" too soon.
The power of substitution treatment has been shown in Zurich, where there has been saturation treatment with methadone and other opioids (including prescribed heroin), accompanied by a marked decrease in heroin use, drug overdose, crime and heroin seizures by police, and an 82% reduction in new heroin users from 850 in 1990 to only 150 in 2002. (Nordt, Stohler. Lancet 2006 367 1830-34).
Another benefit may be if ATS acts like a carrot, getting people with problems to ask for help. A number of people on the waiting list for ATS at St Vincent’s Hospital have improved just with psychosocial interventions while being considered for pharmacotherapy.
Tarra Adam then spoke on her work with amphetamine users at Sydney’s St Vincent’s Hospital. She sees those that present at the hospital with problems related to amphetamine use, or who refer themselves.
Some present with aggression or violence which is out of character and worries them. Many have learnt to manage their use reasonably well, before seeking any treatment.
There is a perception that Alcohol and Drug Services are not for them, and historically these services may have had little to offer. ATS users are often suspicious of the service and whether the service can meet their needs, and may appear to be testing out the therapists, having a strong sense of what they want. Often they wish to be seen in a different area or using a separate entrance, because they are "not like the others".
Amphetamine users do tend to show a different profile, being less impoverished and more educated, motivated but hard to engage, often successful at work with a wide range of social contacts, and in better social circumstances than heroin users. Most are daily users, some injecting 3 times a day, some up to 9 times. The majority of people seen at the St Vincent’s Hospital Stimulant Treatment Program are smoking "crystal". Not many switch between amphetamines and cocaine.
A range of therapies is offered, including Motivational Interviewing, Cognitive Behavioural Therapy, and people may be referred to a “SMART Recovery” group. However CBT may be just too difficult for a person who is chaotic or paranoid, and often experience cognitive impairment during periods of use or whilst in withdrawal. In the early stages of treatment, some people find it difficult to concentrate and connect with how their thoughts and feelings influence their behaviour. In addition, talking about triggers and motivations to change with stimulant users has in our experience, increased people’s craving for the drug and can contribute to ongoing use and/ or relapse. Therefore we concentrate on addressing the wider impact of stimulant use on their sense of self, the impact of use on their relationships, rather than concentrating on the drug use itself.
Therefore, other approaches may be needed, with the aim of trying to engage the person.
Narrative Therapy is an example: here the emphasis is centred on people as the experts in their own lives. It views problems as separate from the person and holds that people come with many skills, beliefs, values and abilities that will assist them to reduce the influence of problems such as stimulants in their lives. People often present to therapy with a problem saturated story that dominates beliefs about themselves and influences the choices they make. Narrative conversations seek out the alternative/ preferred stories –stories that are identified by the person about how they would like to live their lives, what it would mean to them to make these changes and supports them to perform this meaning. The therapist seeks out examples of such stories in their lives which support people to break from the influence of the problems they are facing and create new possibilities for their future by increasing awareness of their skills, beliefs, values, and abilities to reduce the influence of stimulants in their lives. A reference for those interested to know more is "What is Narrative Therapy?" by Alice Morgan (can be ordered from the Dulwich Centre - the link for a summary of her book is: http://www.dulwichcentre.com.au/alicearticle.html)
In the second half, chaired by Dr Bob Batey, a range of case vignettes was discussed.
The first case was a woman who declared "I always shoot speed on my pension day, Doc. It is the only time I ever clean the house … but now all my veins are gone!"
Among the points raised were: possible causes of the exhaustion include following a binge, chronic hepatitis C, and depression. A question was raised about the safety of using antidepressants, including SSRIs, in people who use stimulants, including MDMA. Although this was a theoretical risk, given that these medications and drugs raise monoamine levels in synapses, the expected "epidemic of Serotonin Syndrome has not materialised", as one participant put it. It may be worth suggesting safer ways of administration, as a harm reduction measure, and may be appropriate to refer her for financial management assistance through Centrelink, which offers the Centrepay service for regular payments. It was generally agreed that she was not suitable for AST, given the intermittent nature of her use.
In the second case, a man announced "After I use crystal meth I turn into somebody else. I thought I knew how to fly and jumped off the balcony two storeys up to save using the stairs. Now I’m in plaster with two fractured heels and I can’t even get up those stairs".
Problems like this occur especially with use of other substances as well, such as benzodiazepines, and often end up in jail, or hospital. Once the person settles they may be able to look at their substance use, especially if they are laid up in hospital. An important question is how worried friends or family can help decrease the risk of harms like this: one response is that health professionals need to help "significant others" who seek help in the first instance by helping them look after themselves.
This was also true for the following case, where flatmates sought advice about a young man who had moved in recently from Darlinghurst where "it was too easy to go out every night". He regularly used "ecstasy", took Ritalin for ADD, also selegiline which he read on a web site was good for ADD. He was often up all night, constantly reorganising his room with his things strewn all over the yard. One day he declared angrily "I know you’ve been in my room snooping around. You let things slip that show that you did it. I wish I had video surveillance up there".
Tarra Adam said this was a typical presentation to the Alcohol and Drug Service at St. Vincent's Hospital, except that usually the person absolutely believes that others were doing the video surveillance.
A comment was that nothing could be taken at face value in this case: neither the ADD diagnosis, the precise substances used, nor any other psychiatric diagnosis.
In the next case, a 32 yo man, injecting ATS for 2 years, said: "I'm using ice every day and I can't pull up. Can you give me something to help me detox? Or can I go to a detox somewhere?" Even though the evidence about the amphetamine withdrawal syndrome is limited and there seems to be little benefit from medications, many "detox" facilities will admit amphetamine users. One rehab allows the person to sleep and then clean up, maintaining good hydrations being very important. As many ATS users prefer benzodiazepines to manage their withdrawal, a case could be made in community practice for dispensing a small amount of diazepam to encourage engagement with treatment in future.
The final case was a 34 yo man on MMT for 7 years, 11 years injecting, probably 10 years chronic HCV with fluctuating elevated ALT. His methadone dose was 110 mg and his total testosterone was 5.0 -7.2 mmol/L on repeated (morning) testing. He continued to inject ATS several times a week throughout MMT, saying otherwise he has no energy. He was little motivated to change his ATS use.
The reasons for this man's lack of energy could include hypogonadism (probably from opioids), chronic hepatitis C, depression, or the effect of amphetamines themselves. Among the approaches could be a trial of methadone reductions or androgen replacement (chronic viral hepatitis is not a contraindication for use of testosterone and its esters, which should be used in preference to synthetic androgens). One could offer antiviral treatment for hepatitis C, which may be a motivation to stop injecting drug use (injecting should not be a contraindication for hepatitis C treatment). a trial of antidepressants may be indicated. These strategies should probably be tried serially rather than simultaneously, to avoid diagnostic confusion in the event of an improvement in energy.
Written by Judith Meldrum and Richard Hallinan based on Dr Wodak’s talk.
http://www.redfernclinic.com/
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