Clinical & Policy Updates:
SMMGP Clinical Update June-July 2012
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Examination of mortality rates in a retrospective cohort of patients treated with oral or implant naltrexone for problematic opiate use
Kelty E, Hulse G. Addiction. 2012 May 17. Published online ahead of print
This Australian study looked at data from a community drug treatment clinic and compared patients who took oral naltrexone (n=2155) with those who had implant naltrexone (n=2389) between August 1997 and December 2009. They obtained data from the National Death Index to compare cause-specific mortality rates. All the long-acting naltrexone implants were the O'Neill Long Acting Naltrexone Implant (OLANI) which gives naltrexone levels above therapeutics levels for 145 days before tapering off.
The crude mortality rate for patients given oral naltrexone was 8.78 deaths per 1000 patient-years. The crude mortality rate for those given implant naltrexone was 6.59 deaths per 1000 patient-years. This is a statistically significant difference (p=0.0339). When the first four months of treatment are considered the mortality rate in patients treated with oral naltrexone is 26.28 deaths per 1000 patient-years, yet in the implant naltrexone group it is 7.34 deaths per 1000 patient years. Clearly, this is a highly significant difference and the p-value is %lt;0.0001. This was mostly attributable to overdose deaths - the rate was 25 times greater in the oral naltrexone group compared with the implant treatment group.
SMMGP comment: One of the key issues with naltrexone is the safety of this treatment option. There have been ongoing concerns about naltrexone and the risk of drug overdose - specifically the period when people stop taking naltrexone and have little or no opiate tolerance. There have also been concerns about the risk of depression and suicide secondary to blockade of endogenous opioids. The Russian study published in the Lancet in 2011 showed some efficacy of the naltrexone implant when compared to placebo but lacked safety data.
The difference in the overall mortality rates hinges on the stark difference in the first four months of treatment. The authors state at the end of the abstract that "the use of implant naltrexone can reduce all-cause mortality and opiate overdose during the first four month following treatment compared with patients treated with oral naltrexone." One might need to be a little cautious here given this is a retrospective study - there is a chance it could represent association rather than causation. But it does look mighty impressive. Importantly, it was noted that there was no difference in rates of death from suicide and the overall rates were roughly as expected in this population. This study has the potential to be highly significant - the wary clinician will be very nervous of the overdose risk for those going onto oral naltrexone. The evidence for long-acting implantable naltrexone is building.
Hyperalgesia in heroin dependent patients and the effects of opioid substitution therapy
Compton P, Canamar CP, Hillhouse M, Ling W. J Pain. 2012 Apr.;13(4):401-9
This study in California explored the clinical phenomenon of opioid-induced hyperalgesia. They compared the experimental pain responses in 82 treatment-seeking heroin users who had been randomised to either methadone (n=11) or buprenorphine (n=64), with matched drug free controls (n=21). The heroin-dependent participants were evaluated at baseline, medication stabilisation (4-8 weeks) and also later at 12-18 weeks once stable. The two experimental pain tests were cold pressor (CP) and electrical stimulation (ES). The CP method involves a standardised procedure where the forearm is placed in an ice bath. The ES involves electrical pulses of increasing intensity being applied to the right earlobe.
The results showed that heroin-dependent individuals present in a hyperalgesic state. They then showed that maintenance therapy with methadone or buprenorphine did not significantly change or worsen their pain responses.
Peripartum pain management in opioid dependent women
Höflich AS, Langer M, Jagsch R, Bäowert A, Winklbaur B, Fischer G, et al. Eur J Pain. 2012 Apr.;16(4):574-84
This study investigated the differences in pain management during delivery and in the postpartum period between women who were opioid maintained and those who were non-dependent. They looked at 40 deliveries of 37 opioid dependent women (enrolled in the MOTHER study - a double-blind double-dummy RCT comparing buprenorphine to methadone) and matched them to a non-dependent comparison group of 80 pregnant women.
Following caesarian section the opioid maintained women received significantly less opioid analgesics. NSAIDs were administered more frequently to the opioid dependent group during caesarian section and on day three postpartum. Significantly higher nicotine consumption in the opioid dependent women "had a strong influence" on the results.
SMMGP comment: These two papers neatly put the problem in a nutshell. The first study demonstrates that opioid dependent people experience hyperalgesia. Yet, paradoxically, the second study showed that opioid dependent women were less likely to receive opioid analgesia than the comparison group.
Hyperalgesia has been demonstrated in other studies but the key difference in this one is that the individuals were followed through the induction process while they started on opiate substitution therapy. It's an important point - opiate substitution provides benefits across a range of health and social markers; however, it doesn't seem to improve pain tolerance. The H^flich paper touches on the reasons for inadequate pain relief in clinical practice and it can be summed up in one word: fear. Clinicians fear the combination of side effects when prescribing additional opioids; they fear the risk of provoking relapse; and they fear they are being taken for a ride and manipulated. None of these stand much scrutiny - but we do need to address them if we are to tackle the fundamental disparity these two papers highlight.
A pilot randomised controlled trial of brief versus twice weekly versus standard supervised consumption in patients on opiate maintenance treatment
Holland R, Matheson C, Anthony G, Roberts K, Priyardarshi S, Macrae A, et al. Drug Alcohol Rev. 2012 Jun.;31(4):483-91
This Scottish study wanted to establish if it is feasible to conduct a randomised controlled trial to test the effectiveness of three different models of supervision. The three models they considered were: no supervision but daily pick-up, reduced frequency of supervision (2 days per week); and continued daily supervision. They recruited, across three areas in Scotland, opiatedependent patients who had received methadone treatment for at least 3 months. They were then randomised to one of the three models. In total they achieved their target and 60 people participated in the study. They were able to follow up 46 (77%) of these. They looked at retention rates and illicit heroin use.
They noted that those recruited to the "no supervision" group were the happiest with their allocation. This study was never intended to have sufficient power to give definitive answers but there were some trends in the results. No statistically significant differences were found in the outcomes but the data suggest that increased supervision may reduce illicit heroin use while decreasing retention.
SMMGP comment: This was a pilot study; the primary aim was to see if it's feasible to do a wider study. The authors highlight the lack of hard evidence and supervision remains a contentious area in clinical practice that needs careful balancing. The evidence suggests it has been associated with a reduction in methadone-related deaths and the current national guidelines suggest a minimum period of 12 weeks from initiation. Yet, it is often interpreted by people as being punitive and it doesn't help to load stigma on individuals who are trying to move away from drugtaking peers and social groups.
Little substantive value can be put in the results from this pilot but the initial findings will chime with clinicians. While supervision is an important mechanism in the first stages of treatment it is important it is reviewed early and the pragmatic clinician will usually be keen to give responsibility back to the individual wherever possible.
The association between alcohol use and hepatitis C status among injecting drug users in Glasgow
O'Leary MC, Hutchinson SJ, Allen E, Palmateer N, Cameron S, Taylor A, et al. Drug Alcohol Depend. 2012 Jun. 1;123(1-3):180-9
This study was a repeat of a cross-sectional survey of IDUs who were accessing harm reduction services in Glasgow between 2005 and 2007. They measured selfreported weekly alcohol consumption, excess drinking (exceeding 14u/week for women and 21u/week for men) and HCV antibodies (done anonymously via oral fluid samples).
The results showed that amongst those who tested positive for hepatitis C virus (HCV) antibodies, 65% drank alcohol and 29% exceeded the safe limits. This compared to the figures for those who tested negative where 61% drank alcohol (not a statistically significant difference) but 18% exceeded safe limits (highly significant at p<0.001). Those who self-reported being HCV positive were less likely to drink but just as likely to drink to excess. In those who were HCV positive, excess drinking was associated with incarceration and homelessness.
Efficacy of chronic hepatitis C therapy with pegylated interferon and ribavirin in patients on methadone maintenance treatment
Neukam K, Mira JA, Gilabert I, Claro E, Vázquez MJ, Cifuentes C, et al. Eur. J. Clin. Microbiol. Infect. Dis. 2012 Jun.;31(6):1225-32
This was a Spanish study that compared the response rates to HCV treatment in patients with or without methadone maintenance treatment. A total of 214 patients were included in the study - 81 on methadone maintenance and 133 who weren't. They noted that there were no differences between HCV genotype distribution between the two groups. In total 103 out of 214 patients (48%) achieved the desired sustained virological response (SVR). The percentage who got to SVR was identical between the methadone group and the non-methadone group. The frequency of drop-outs and treatment discontinuations were also comparable with no significant differences.
SMMGP comment: The Scottish study demonstrates that, even in the presence of HCV, there remain problems with people drinking to excess, particularly alongside deep-rooted social issues such as homelessness. Many of those who were HCV positive had cut down on their drinking - and those who are drinking to excess have to be put in the context of a Scottish society with an ingrained drinking culture. Perhaps more alarmingly, it noted that half of those who were positive simply didn't know their status.
On a more positive note, the Spanish study is a timely reminder to clinicians and services involved in the treatment of HCV that it isn't a futile enterprise. People can do well in treatment, despite all the complexities associated with HCV infection. The evidence isn't completely one-sided - other studies have shown concerns about treatment success rates in those on opiate substitution therapy. And everyone working in the field will be fully aware of the huge pool of HCV infections that aren't getting anywhere near treatment. But, for those who get there, there is evidence to suggest they do just as well. That's some cause for optimism.
Routine exposure to blood within hostel environments might help to explain elevated levels of hepatitis C amongst homeless drug users: insights from a qualitative study
Neale J, Stevenson C. Int J Drug Policy. 2012 May;23(3):248-50
This short report looked at the issue of hepatitis C in homeless drug users. The original study involved semistructured qualitative interviews with 40 homeless drug users. These were conducted in 2010/11 and the participants were either staying, or had stayed within the last six months, in emergency hostels or night shelters. In total, 56 separate hostels were involved across a range of areas in England, including five relatively small towns and one large city. The aim was to explore the support needs of those staying in emergency hostels or night shelters but the authors reported that blood emerged as an unexpected recurring topic within these interviews. They took all the blood data, coded and analysed this inductively.
The results showed that spilt and dried blood were "routine features of hostel life". The problem seemed to be greater in larger night shelters where there was a large number of transient residents with complex drug, alcohol and mental health problems. Many of the accounts of spilt and dried blood were related to injecting and problems with inadequate facilities to dispose of sharps. One hostel resident reported: "You have to expect some blood and needles. It's not the Hilton."
Venous access and care: harnessing pragmatics in harm reduction for people who inject drugs
Harris M, Rhodes T. Addiction. 2012 Jun.;107(6):1090-6
This was another qualitative study that aimed to explore the factors that help with long-term hepatitis C avoidance among people who inject drugs. They recruited through low-threshold drug services and networks in the South East and London. The sample included 35 people and 20 of them were hepatitis C antibody-negative. The average length of time they had been injecting was 19 years with two-thirds primarily injecting just heroin and the rest crack/heroin.
Participants expressed a desire, currently unmet, for non-judgemental venous access information and advice. They reported that the loss of peripheral veins and the risks associated with a transition to groin injecting were of primary concern. Advice and information on avoiding venous sclerosis and how to find and safely access less visible veins were desired by the majority.
SMMGP comment: It has been shown that homelessness is a key risk factor for HCV infection amongst injecting drug users. It seems wrong that anyone should have to accept "some blood and needles" but the authors reported that there was general appreciation amongst many residents of the difficulties staff and organisations faced. Not all hostels or shelters had this problem but overall, there is a clear message that hostel facilities need appropriate professional cleaning support. It reinforces the need for clinicians to ensure they are testing regularly for bloodborne viruses, they are immunising all, including non-injectors, for hepatitis B and they are providing education to increase awareness of the risks amongst users of hostels.
The second paper puts a slightly different slant on the harm reduction advice that many users report. Sometimes the advice to "try smoking" simply won't be hitting the spot when people are struggling with venous access. A video with the principal author of this paper, Magdalena Harris, talking openly about her experiences of harm reduction can be viewed in the Featured Videos section.
Evidence-based guidelines for the pharmacological management of substance abuse, harmful use, addiction and comorbidity: recommendations from BAP
Lingford-Hughes AR, Welch S, Peters L, Nutt DJ. J Psychopharmacol. 2012 May 23
The British Association for Psychopharmacology guidelines have been revised since their initial publication in 2004. They are solely concerned with pharmacological management and cover topics such as: alcohol, nicotine, opioids, benzodiazepines, stimulants and associated comorbidity with mental health issues and substance use in pregnancy. They also touch on some of the issues relating to medications for younger and older users, as well as those with personality disorders, club drugs, cannabis and polydrug users.
SMMGP comment: There are few areas these guidelines don't cover and they make a fine reference document. In many ways, this paper, which runs to over 54 pages and with well over 500 references, is best thought of as a concise reference text. They deserve to be printed, bound and kept handy for anyone involved in managing substance misuse problems. Recommended.
After the randomised injectable opiate treatment trial: Post-trial investigation of slow-release oral morphine as an alternative opiate maintenance medication
Bond AJ, Reed KD, Beavan P, Strang J. Drug Alcohol Rev. 2012 Jun.;31(4):492-8
The "randomised injectable opiate treatment trial" referred to in this title is the RIOTT study published in the Lancet in 2010. This was an investigation into the use of injectables for those who were treatmentresistant to oral methadone. In RIOTT individuals were allocated to three arms: diamorphine injection + oral methadone; injectable hydromorphone + oral methadone; and oral methadone alone. All the groups were on oral methadone to ensure 24 hour stability. Concerns about the use of oral methadone continued and this new study reports on twelve of the patients from the RIOTT study who were introduced to slowrelease oral morphine (SROM) as an alternative oral maintenance medication. The SROM was substituted for oral methadone by cross-titration. There was a case note review of interviews and medication details before and after change in medication.
The participants had reported a dislike and intolerance of methadone but had positive expectations of SROM. The mean stable methadone: SROM medication ratio was 1:7.5. After 10 weeks' SROM treatment, the average daily diamorphine dose reduced from 382mg to 315mg with patients reporting fewer cravings and improved sleep and wellbeing.
SMMGP comment: The numbers are small in this study and this is a specialist intervention that won't be relevant to many primary care providers. However, it is common to meet people who would be keen to explore alternatives to methadone or buprenorphine. This is not a randomised controlled study - it's simply a retrospective review of case notes in a small group of patients. In addition, these patients have, as fully described by the authors, clear views about methadone. There are numerous ways that bias could be manifest. It was clear that there wasn't a strict intolerance in all cases - for many it was a simple dislike.
The new British Association for Psychopharmacology guidelines highlight that, overall, there are only a small number of short-term studies looking at SROM. In these, similar effectiveness to methadone has been shown but no long term data are available. They also noted that the experience in Austria is that SROM is "frequently abused and dominates the black market". However, although there remains interest in the use of alternatives to break the hegemony of methadone and buprenorphine - it's going to take a big study to make SROM a realistic option.
Publication of the final Report from the Recovery Oriented Drug Treatment Expert Group facilitated by the NTA on: Medications in Recovery: Re-orientating Drug Dependence Treatment.
A group of leading doctors and other experts in drug dependence last week launched a significant report (click here for the PDF on the NTA web site) on the ways in which prescribing medication can help heroin users break the hold of addiction and recover from dependence.
The report is the product of a two-year inquiry by GPs, psychiatrists, psychologists, nurses, service users, and providers
from both the NHS and voluntary sectors. It was chaired by one of Britain's leading addiction specialists, Prof John Strang of the National Addiction Centre.
A discussion about the report was started last week on the SMMGP forums, and we will comment on the report more fully in a future Clinical/Policy Update. In the meanwhile, if you have any comment to make on this report, please add to the thread on the forums.