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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.