Can dihydrocodeine reduce illegal opiate use in adolescents and adults?

Review question

We reviewed evidence on the effects of dihydrocodeine (DHC) to reduce illegal substance use among adolescents older than 15 years and adults.

Background

The use of illegal substances such as heroin is a world-wide problem, and can lead to other issues. What is especially concerning is the far-reaching health consequences of this substance use. This includes high numbers of deaths due to heroin and other opiates from overdoses, and the fact that it is a risk factor for Hepatitis C and HIV, particularly among those who inject their drugs.

We wanted to learn if DHC has a positive effect on decreasing this kind of drug use among those adolescents and adults. DHC is a type of opiate that is codeine-based.

Search date

The evidence is current to February 2019.

Study characteristics

We included three studies in this review with 385 participants in total with follow-up periods of different length. Two studies with 150 participants compared DHC to buprenorphine for detoxification (managing physical symptoms of withdrawal), while one study with 235 individuals compared DHC to methadone for maintenance substitution therapy (providing legal substance to reduce risk behaviour and other harm related to drug use over a longer period). All the studies took place in the UK.

Our primary outcome was abstinence or no longer using illegal substances; our secondary outcomes were completing treatment, as well as health-related consequences of substance use, and other behaviours often linked to substance use such as illegal activity. We also assessed the safety of DHC.

Key results

For detoxification from illegal substances such as heroin, DHC may not work any better than buprenorphine in reducing substance use, keeping individuals in treatment and other behaviours. The pattern stayed the same for follow-up appointments.

For maintenance treatment, DHC also may not work better than methadone in reducing substance use or any of the secondary outcomes, but participants may be more likely to stay in treatment. This finding remained the same across longer follow-up periods as well.

The only adverse event reported was one death from a methadone overdose in the study that compared DHC with methadone as maintenance therapy.

The pattern of results indicates that individuals who received DHC generally may not do better in reducing their substance use, completing treatment or other measures of substance-related behaviours than those that received other types of medication. However it is premature to make definitive statements about the efficacy of DHC for reducing illegal substance use, due to the low quality of evidence.

Quality of evidence

Overall, the evidence was of low quality. There were two major issues across the studies. There was no blinding of the participants or those who assessed the outcomes, so that they were aware of which group they were in. There was also a high level of participants who dropped out of two of the studies.

Study funding sources

All three studies were funded by government or research foundation organisations.

Authors' conclusions: 

We found low-quality evidence that DHC may be no more effective than other commonly used pharmacological interventions in reducing illicit opiate use. It is therefore premature to make any conclusive statements about the effectiveness of DHC, and it is suggested that further high-quality studies are conducted, especially in low- to middle-income countries.

Read the full abstract...
Background: 

Medical treatment and detoxification from opiate disorders includes oral administration of opioid agonists. Dihydrocodeine (DHC) substitution treatment is typically low threshold and therefore has the capacity to reach wider groups of opiate users. Decisions to prescribe DHC to patients with less severe opiate disorders centre on its perceived safety, reduced toxicity, shorter half-life and more rapid onset of action, and potential retention of patients. This review set out to investigate the effects of DHC in comparison to other pharmaceutical opioids and placebos in the detoxification and substitution of individuals with opiate use disorders.

Objectives: 

To investigate the effectiveness of DHC in reducing illicit opiate use and other health-related outcomes among adults compared to other drugs or placebos used for detoxification or substitution therapy.

Search strategy: 

In February 2019 we searched Cochrane Drugs and Alcohol's Specialised Register, CENTRAL, PubMed, Embase and Web of Science. We also searched for ongoing and unpublished studies via ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and Trialsjournal.com. All searches included non-English language literature. We handsearched references of topic-related systematic reviews and the included studies.

Selection criteria: 

We included randomised controlled trials that evaluated the effect of DHC for detoxification and maintenance substitution therapy for adolescent (aged 15 years and older) and adult illicit opiate users.

The primary outcomes were abstinence from illicit opiate use following detoxification or maintenance therapy measured by self-report or urinalysis. The secondary outcomes were treatment retention and other health and behaviour outcomes.

Data collection and analysis: 

We followed the standard methodological procedures that are outlined by Cochrane. This includes the GRADE approach to appraise the quality of evidence.

Main results: 

We included three trials (in five articles) with 385 opiate-using participants that measured outcomes at different follow-up periods in this review. Two studies with 150 individuals compared DHC with buprenorphine for detoxification, and one study with 235 participants compared DHC to methadone for maintenance substitution therapy. We downgraded the quality of evidence mainly due to risk of bias and imprecision.

For the two studies that compared DHC to buprenorphine, we found low-quality evidence of no significant difference between DHC and buprenorphine for detoxification at six-month follow-up (risk ratio (RR) 0.59, 95% confidence interval (CI) 0.25 to 1.39; P = 0.23) in the meta-analysis for the primary outcome of abstinence from illicit opiates. Similarly, low-quality evidence indicated no difference for treatment retention (RR 1.29, 95% CI 0.99 to 1.68; P = 0.06).

In the single trial that compared DHC to methadone for maintenance substitution therapy, the evidence was also of low quality, and there may be no difference in effects between DHC and methadone for reported abstinence from illicit opiates (mean difference (MD) −0.01, 95% CI −0.31 to 0.29). For treatment retention at six months' follow-up in this single trial, the RR calculated with an intention-to-treat analysis also indicated that there may be no difference between DHC and methadone (RR 1.04, 95% CI 0.94 to 1.16).

The studies that compared DHC to buprenorphine reported no serious adverse events, while the DHC versus methadone study reported one death due to methadone overdose.

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