Insomnia and excessive daytime sleepiness in women and men receiving methadone and buprenorphine maintenance treatment.

Background: Insomnia and excessive daytime sleepiness (EDS) are reported to be common in methadone maintenance treatment (MMT) but much less is known about these symptoms in buprenorphine maintenance treatment (BMT) and in women compared with men. Methods: Cross sectional study of recipients of BMT (n = 113, 47 women), MMT (n = 184, 94 women), people using opioids nonmedically (nonopioid agonist treatment, non-OAT: n = 87, 31 women) and a reference group with no opioid use (RG; n = 105, 53 women) in Australia. Measures included Athens Insomnia Scale, Epworth Sleepiness Scale, the Hospital Anxiety and Depression Scale, and other substance use. Results: Insomnia (Athens Insomnia Scale, total ≥10) was highly prevalent among all people who use opioids (BMT 46.0-68.1%; MMT 55.4-69.6%; non-OAT 58.6-80.5%), did not differ significantly among these groups, and was significantly associated with anxiety and depression. EDS (Epworth score >10) was found in 14.2% of BMT, 22.8% of MMT, 35.6% of non-OAT groups, and 11.4% of the RG, and was significantly associated with depression overall. Fewer people had Epworth score >15 indicating more severe EDS (BMT 4.4%, MMT 6.0%; non-OAT 13.8%; RG 1.9%). Insomnia and EDS did not differ by sex or by opioid dose, nor were they significantly associated with other drug use, housing stress or social security status. Conclusions: Insomnia was common in people receiving OAT and using opioids non-medically, and associated with anxiety and depression. Clinicians should consider the possibility of daytime sleepiness in people receiving BMT and MMT, and in people using opioids nonmedically.

Cannabis and benzodiazepines as determinants of methadone trough plasma concentration variability in maintenance treatment: a transnational study.

PURPOSE: To assess tobacco, alcohol, cannabis and benzodiazepine use in methadone maintenance treatment (MMT) as potential sources of variability in methadone pharmacokinetics. METHODS: Trough plasma (R)- and (S)-methadone concentrations were measured on 77 Australian and 74 Swiss MMT patients with no additional medications other than benzodiazepines. Simple and multiple regression analyses were performed for the primary metric, plasma methadone concentration/dose. RESULTS: Cannabis and methadone dose were significantly associated with lower 24-h plasma (R)- and (S)-methadone concentrations/dose. The models containing these variables explained 14-16% and 17-25% of the variation in (R)- and (S)-methadone concentration/dose, respectively. Analysis of 61 patients using only CYP3A4 metabolised benzodiazepines showed this class to be associated with higher (R)-concentration/dose, which is consistent with a potential competitive inhibition of CYP3A4. CONCLUSION: Cannabis use and higher methadone doses in MMT could in part be a response to-or a cause of-more rapid methadone clearance. The effects of cannabis and benzodiazepines should be controlled for in future studies on methadone pharmacokinetics in MMT.

Erectile dysfunction in men receiving methadone and buprenorphine maintenance treatment.

INTRODUCTION: Use of opiates/opioids is associated with hypoactive sexual desire, erectile and orgasmic dysfunction. AIM: To determine prevalence and investigate etiology of sexual dysfunction in men on methadone or buprenorphine maintenance treatment (MMT, BMT). MAIN OUTCOME MEASURES: International Index of Erectile Function (IIEF), hormone assays, Beck Depression Inventory. METHODS: A total of 103 men (mean age 37.6 +/- 7.9) on MMT (N = 84) or BMT (N = 19) were evaluated using the IIEF, hormone assays, Beck Depression Inventory, body mass index (BMI), demographic, and other substance use measures. RESULTS: Mean total IIEF scores for partnered men were lower for MMT (50.4 +/- 18.2; N = 53) than reference groups (61.4 +/- 16.8; N = 415; P < 0.0001) or BMT (61.4 +/- 7.0; N = 14; P = 0.048). Among partnered men on MMT, 53% had erectile dysfunction (ED) compared with 24% of reference groups; 26% had moderate to severe ED, 12.1% in under 40s and 40.0% among those 40+ years. On multiple regression, depression, older age, and lower total testosterone were associated with lower IIEF and EF domain; on multivariate analysis, there were no significant associations between IIEF or EF and free testosterone, opioid dose, cannabis or other substance use, viral hepatitis, or BMI. Total testosterone accounted for 16% of IIEF and 15% of EF variance. Men without sexual partners had lower Desire and Erection Confidence scores and less recent sexual activity, suggesting potentially higher prevalence of sexual dysfunction in this group. CONCLUSION: Men on MMT, but not BMT, have high prevalence of ED, related to hypogonadism and depression. Practitioners should screen for sexual dysfunction in men receiving opioid replacement treatment. Future studies of sexual dysfunction in opioid-treated men should examine the potential benefits of dose reduction, androgen replacement, treatment of depression, and choice of opioid.

Referral for chronic hepatitis C treatment from a drug dependency treatment setting.

To examine rates and predictors of referral for hepatitis C virus (HCV) treatment and preliminary treatment outcomes in injecting drug users (IDUs) receiving opioid replacement treatment, a prospective clinical audit was undertaken in an inner city Sydney drug dependency treatment practice between December 2002 and November 2005. The majority of IDUs (178/237; 75%) were HCV antibody positive, of whom 170 were HCV treatment naïve with no absolute treatment contraindications. Among these 170 patients, 121 (71%) had chronic HCV. Based on risk factors for HCV disease progression, 63 of 121 (52%) chronic HCV patients were targeted for referral; these patients were older, had higher alanine aminotransferase levels and longer estimated duration of HCV infection. Of these 63 patients, 43 were referred to a hepatitis treatment clinic, and 27 attended during the audit period. Patients who attended for treatment assessment were more likely to have genotype 2 or 3 (p<0.001), but socio-behavioural factors were similar. Liver biopsy was performed in 20 patients, with moderate or greater fibrosis in 18 patients. Of 14 patients commenced on pegylated interferon-alpha and ribavirin therapy, one ceased treatment due to non-response, 10 have completed treatment, all with an end-of-treatment (n=4) or sustained virological response (n=6), and treatment is ongoing in three. The development of HCV treatment referral criteria has allowed prioritisation of patients for referral, potentially halving those that require early assessment. Preliminary HCV treatment outcomes are encouraging and highlight the potential for reducing liver disease burden in this patient population.

Harm reduction, hepatitis C and opioid pharmacotherapy: an opportunity for integrated hepatitis C virus-specific harm reduction.

While harm reduction advocates, policy makers and practitioners have a right to be proud of the impact of interventions such as needle and syringe programmes on HIV risk, we can be less sanguine about the ongoing high levels of HCV transmission among injecting drug users (IDUs) and the expanding burden of hepatitis C virus (HCV)-related liver disease. In this Harm Reduction Digest Drs Byrne and Hallinan from the Redfern Clinic and Dr Dore from the National Centre in HIV Epidemiology and Clinical Research offer a model of integrated HCV prevention and treatment services within the setting of opioid pharmacotherapy. In their experience, this common-sense approach provides an opportunity to reduce the burden of HCV and improve overall patient management. They believe that the key elements of a HCV-specific harm reduction model include: regular HCV testing; clinical assessment and determination of need for HCV treatment referral; use of broader HCV treatment inclusion criteria; and flexibility in opioid pharmacotherapy dosing. In an environment when our macro harm reduction interventions seem to have, at best, modest impact on HCV transmission, good clinical practice may be our most effective strategy against the HCV epidemic. This paper provides some practical suggestions as to how this can be done.

Constipation and other common symptoms reported by women and men in methadone and buprenorphine maintenance treatment.

BACKGROUND: Opioid substitution treatment (OST) is often continued long-term and, therefore, opioid-associated symptoms are of interest. Symptoms associated with methadone maintenance treatment (MMT) in men are well described, but there are fewer reports concerning symptoms associated with buprenorphine maintenance treatment (BMT) and very few reports among women. METHOD: Recipients of BMT (n=113) and MMT (n=184), non-opioid users (n=105) and opioid users not receiving OST (n=87) completed the Patient Assessment of Constipation (PAC-SYM) and a general symptom checklist. Multivariate analysis included other potential moderators of opioid-associated symptoms. FINDINGS: Opioid users reported a higher frequency and severity of symptoms than non-opioid users. Constipation, dry mouth, decreased appetite, sweating and fatigue were highly prevalent in the previous 30days (51-80%). Nausea, itchy skin, trouble urinating, menstrual problems, lightheadedness, blurred vision, heart racing were also common (30-50%). Non-OST opioid users had significantly higher frequency and severity than OST recipients of nausea, vomiting, diarrhoea, decreased appetite, sweating and itchy skin. Sweating was significantly more common in MMT than BMT. Constipation scores were higher in women, otherwise most sex differences were small. Higher PAC-SYM scores were associated with vomiting (OR=1.04) and sweating (OR=1.06). Cannabis use was associated with vomiting (OR=2.19). Constipation (OR=1.07), insomnia (OR=2.5) and depression (OR=2.82) were associated with fatigue. CONCLUSION: Men and women receiving OST report similarly high rates of somatic symptoms, though less than opioid users not receiving OST. There were few differences between BMT and MMT. Buprenorphine might be preferred where sweating is problematic. Several modifiable factors were identified.

Therapeutic thresholds in methadone maintenance treatment: a receiver operating characteristic analysis.

Twenty-four-hour trough (R)- and (R,S)-methadone plasma concentrations were measured on 94 methadone maintenance treatment (MMT) patients classified as 'responders' or 'non-responders', based on urine toxicology evidence of recent illicit opiate use. Receiver operating characteristic (ROC) curves for daily dose, dose/bodyweight, and (R)- and (R,S)-methadone trough plasma concentrations were used to identify optimal thresholds; areas under the curve (AUC) were used to compare predictive power. Non-responders (n=37) had a lower mean dose (73 mg/day versus 147 mg/day; p<0.001), (R)-methadone concentration (136 ng/ml versus 223 ng/ml; p<0.005) and (R,S)-methadone concentration (266 ng/ml versus 409 ng/ml; p=0.001) than responders. On multivariate regression, duration of treatment and methadone dose were significantly associated with treatment response. After backward stepwise regression, each year of treatment increased the odds of abstinence from illicit opioid use by 34% (OR 1.34; 95% CI 1.14-1.57)); each 20mg of methadone dose by 36% (OR 1.36 CI; 95% CI 1.11-1.67). On ROC analysis, AUC for daily dose (0.77, 95% CI 0.68-0.87), dose/bodyweight (0.76, 95% CI 0.66-0.85), (R)-methadone (0.73, 95% CI 0.63-0.84) and (R,S)-methadone concentration (0.70, 95% CI 0.59-0.81) did not differ significantly. Dose/bodyweight, and trough plasma concentrations of (R)- or (R,S)-methadone were no better predictors of treatment response than daily dose, and did not improve the fit of the model for treatment outcome as judged by the likelihood ratio test (p=0.21, 0.88, and 0.97, respectively). Optimal therapeutic thresholds (sensitivity, specificity) were: daily dose 100mg/day (67%, 81%); (R)-methadone 200 ng/ml (51%, 78%); (R,S)-methadone 400 ng/ml (40%, 81%). Thresholds with specificity near 90% (dose 140 mg/day; (R)-methadone 250 ng/ml; (R,S)-methadone 500 ng/ml) may help guide dose titration for patients continuing to use illicit opiates.

Hepatitis C virus incidence among injecting drug users on opioid replacement therapy.

OBJECTIVE: To determine hepatitis C virus (HCV) incidence among injecting drug users (IDUs) receiving opioid replacement therapy (ORT). METHODS: A retrospective cohort study was established in a primary care drug dependency treatment clinic. The cohort included all IDUs who commenced ORT after January 1996 with an initial anti-HCV antibody negative result and repeat testing prior to July 2003. HCV incidence was estimated for all subjects, with further comparison among those with continuous versus interrupted ORT. RESULTS: Fifty-four subjects were initially HCV antibody negative and had repeat testing. Five cases of HCV antibody seroconversion occurred during a total follow-up period of 131.1 person years (py), an incidence of 3.8/100 py (95% CI 1.2-8.9/ 100 py). Four seroconversions occurred in the subgroup with interrupted ORT (n=20), an incidence of 7.4/100 py (95% CI 2.0-18.9/100 py), compared with one seroconversion in the subgroup with continuous ORT (n=34), an incidence of 1.3/100 py (95% CI 0.03-7.3/100 py). CONCLUSIONS: HCV incidence among IDUs receiving ORT in our clinic was relatively low. Those IDUs without interruptions to their treatment appeared to be at particularly low risk of HCV infection. These findings support the role of ORT in HCV prevention for IDUs.

Delivery of treatment for hepatitis C virus infection in the primary care setting.

OBJECTIVES: The aim of this study was to evaluate the feasibility, safety and efficacy of treatment for chronic hepatitis C virus (HCV) infection through a primary care-based model for the delivery of HCV services in New South Wales (NSW), Australia. PARTICIPANTS AND METHODS: This observational cohort study recruited participants through seven primary care clinics in NSW, Australia, between November 2010 and June 2013. Patients with HCV genotype 2/3 were treated without specialist review, whereas those with genotype 1 required an initial specialist review. Treatment consisted of pegylated interferon-α-2a/2b and ribavirin. Sustained virological response and adverse events were evaluated. RESULTS: Among 41 participants (mean age 44 years, 73% men) initiating treatment with pegylated interferon-α-2a/2b and ribavirin, 90% had injected drugs ever, 16% had injected drugs in the past 30 days and 56% had ever received opioid substitution treatment. HCV genotype 1 and genotype 2/3 occurred in 17% (n=7) and 83% (n=34). Treatment was completed in 83% (34 of 41), with seven discontinuations [adverse event (depression), n=1; patient decision, n=1; lost to follow-up, n=3; virological nonresponse, n=2]. In an intent-to-treat analysis, sustained virological response was 71% overall (29 of 41), 43% in genotype 1 (three of seven) and 76% in genotype 2/3 (26 of 34). CONCLUSION: Initiation of HCV treatment in the primary care setting is an effective alternative for selected patients and may contribute towards increasing access to HCV care.

ABCB1 haplotype and OPRM1 118A > G genotype interaction in methadone maintenance treatment pharmacogenetics.

BACKGROUND: Genetic variability in ABCB1, encoding the P-glycoprotein efflux transporter, has been linked to altered methadone maintenance treatment dose requirements. However, subsequent studies have indicated that additional environmental or genetic factors may confound ABCB1 pharmacogenetics in different methadone maintenance treatment settings. There is evidence that genetic variability in OPRM1, encoding the mu opioid receptor, and ABCB1 may interact to affect morphine response in opposite ways. This study aimed to examine whether a similar gene-gene interaction occurs for methadone in methadone maintenance treatment. METHODS: Opioid-dependent subjects (n = 119) maintained on methadone (15-300 mg/day) were genotyped for five single nucleotide polymorphisms of ABCB1 (61A > G; 1199G > A; 1236C > T; 2677G > T; 3435C > T), as well as for the OPRM1 118A > G single nucleotide polymorphism. Subjects' methadone doses and trough plasma (R)-methadone concentrations (C(trough)) were compared between ABCB1 haplotypes (with and without controlling for OPRM1 genotype), and between OPRM1 genotypes (with and without controlling for ABCB1 haplotype). RESULTS: Among wild-type OPRM1 subjects, an ABCB1 variant haplotype group (subjects with a wild-type and 61A:1199G:1236C:2677T:3435T haplotype combination, or homozygous for the 61A:1199G:1236C:2677T:3435T haplotype) had significantly lower doses (median ± standard deviation 35 ± 5 versus 180 ± 65 mg/day, P < 0.01) and C(trough) (78 ± 22 versus 177 ± 97 ng/mL, P < 0.05) than ABCB1 wild-type subjects. Among subjects with the most common ABCB1 haplotype combination (wild-type with 61A:1199G:1236T:2677T:3435T), the OPRM1 118 A/G genotype was associated with a significantly higher C(trough) than 118 A/A (250 ± 126 versus 108 ± 36 ng/mL, P = 0.016). No ABCB1 haplotype group or OPRM1 genotype was associated with dose or C(trough) without taking into account confounding genetic variability at the other locus. Therefore, two interacting pharmacogenetic determinants of methadone maintenance treatment response were identified, ie, ABCB1, where variants are associated with lower methadone requirements, and OPRM1, where the variant is associated with higher methadone requirements. CONCLUSION: These opposing pharmacogenetic effects therefore need to be considered in combination when assessing methadone maintenance treatment pharmacogenetics.

Increasing the benefits and reducing the harms of prescription opioid analgesics.

ISSUES: Consumption of prescription opioid analgesics (POAs) in Australia has increased steadily in recent years, raising concerns of increasing harms including overdose and dependence, as has occurred in the USA. APPROACH: Exposition of the Royal Australasian College of Physicians Prescription Opioid Policy with reference to the published literature, drawing out principles for harm reduction for psychoactive pharmaceutical drugs. KEY FINDINGS: Complex professional, patient, regulatory and market factors influence health professionals balancing the benefits and harms of POAs. Owing to the potential for diversion, overlapping markets probably exist for pharmaceutical opioids used for populations with cancer pain, chronic non-cancer pain, and people dependent on pharmaceutical and illicit opioids (including those needing opioid substitution treatment). Attempts to reduce or restrict supply in one area may increase demand in others. There is a need to consider new harm reduction strategies for people with problematic pharmaceutical opioid use. These people are demographically not well characterised, and may be distinct from the more familiar population of injection drug users. IMPLICATIONS: Harm reduction is a valid approach for POAs. However, the role of health professionals as gatekeepers of opioid supply, the need to optimise health benefits of POAs, and the likely interplay of complex market forces among populations consuming opioids have no close parallel in harm reduction for other substances. This poses fundamentally different challenges. CONCLUSIONS: Reducing inappropriate supply and demand for POAs while maximising their benefits and minimising their harms may improve health outcomes.

Improving the management of chronic non-malignant pain and reducing problems associated with prescription opioids.

New guidelines and a multidisciplinary approach have the potential to help patients in need while minimising inappropriate use of opioids.

Hepatitis C virus prevalence and outcomes among injecting drug users on opioid replacement therapy.

OBJECTIVES: To determine hepatitis C virus (HCV) prevalence among injecting drug users (IDUs) receiving opioid replacement therapy in a referred office setting, and assess potential needs for hepatitis C treatment and care. METHODS: Data were collected on 178 IDUs receiving opioid replacement therapy who underwent clinical assessment between January 2002 and June 2003. Standard clinic protocols included HCV and hepatitis B virus (HBV) serology, liver biochemistry and HCV RNA analysis for patients with a positive HCV antibody and normal alanine aminotransferase (ALT) levels. RESULTS: HCV prevalence was 75.3%, similar for males (75.5%) and females (74.4%), and increased with age from 60.8% for 19-30 years to 93.9% above 40 years. Among patients with HCV antibodies and no prior HCV antiviral therapy (n = 130), 53.1% had normal ALT levels and 25.4% were HCV-RNA negative. Older patients were more likely to have normal ALT levels (P = 0.02), and be HCV-RNA negative (P = 0.02). Younger patients were more likely to have been HBV vaccinated (P < 0.001), however, were less likely to have either vaccine or natural immunity (P = 0.006). Of 97 patients with probable chronic HCV infection, 58 patients met pre-liver biopsy criteria for HCV treatment, 34 had relative contraindications to treatment and 6 had been referred for treatment assessment. CONCLUSION: Clinical characterization in a setting of high HCV prevalence has enabled the differentiation of patients into groups with no evidence of HCV viraemia, with chronic HCV infection, and those most appropriate for HCV treatment referral. These clinical assessments along with appropriate referral should be instituted in drug dependency treatment settings.