Clinician Article

Adverse events associated with medium- and long-term use of opioids for chronic non-cancer pain: an overview of Cochrane Reviews.

  • Els C
  • Jackson TD
  • Kunyk D
  • Lappi VG
  • Sonnenberg B
  • Hagtvedt R, et al.
Cochrane Database Syst Rev. 2017 Oct 30;10:CD012509. doi: 10.1002/14651858.CD012509.pub2. (Review)
PMID: 29084357
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  • Family Medicine (FM)/General Practice (GP)
    Relevance - 7/7
    Newsworthiness - 4/7
  • General Internal Medicine-Primary Care(US)
    Relevance - 7/7
    Newsworthiness - 4/7
  • Special Interest - Pain -- Physician
    Relevance - 7/7
    Newsworthiness - 4/7
  • Public Health
    Relevance - 6/7
    Newsworthiness - 6/7
  • Internal Medicine
    Relevance - 6/7
    Newsworthiness - 5/7
  • Neurology
    Relevance - 6/7
    Newsworthiness - 3/7
  • Rheumatology
    Relevance - 6/7
    Newsworthiness - 3/7
  • FM/GP/Mental Health
    Relevance - 5/7
    Newsworthiness - 5/7


BACKGROUND: Chronic pain is common and can be challenging to manage. Despite increased utilisation of opioids, the safety and efficacy of long-term use of these compounds for chronic non-cancer pain (CNCP) remains controversial. This overview of Cochrane Reviews complements the overview entitled 'High-dose opioids for chronic non-cancer pain: an overview of Cochrane Reviews'.

OBJECTIVES: To provide an overview of the occurrence and nature of adverse events associated with any opioid agent (any dose, frequency, or route of administration) used on a medium- or long-term basis for the treatment of CNCP in adults.

METHODS: We searched the Cochrane Database of Systematic Reviews (the Cochrane Library) Issue 3, 2017 on 8 March 2017 to identify all Cochrane Reviews of studies of medium- or long-term opioid use (2 weeks or more) for CNCP in adults aged 18 and over. We assessed the quality of the reviews using the AMSTAR criteria (Assessing the Methodological Quality of Systematic Reviews) as adapted for Cochrane Overviews. We assessed the quality of the evidence for the outcomes using the GRADE framework.

MAIN RESULTS: We included a total of 16 reviews in our overview, of which 14 presented unique quantitative data. These 14 Cochrane Reviews investigated 14 different opioid agents that were administered for time periods of two weeks or longer. The longest study was 13 months in duration, with most in the 6- to 16-week range. The quality of the included reviews was high using AMSTAR criteria, with 11 reviews meeting all 10 criteria, and 5 of the reviews meeting 9 out of 10, not scoring a point for either duplicate study selection and data extraction, or searching for articles irrespective of language and publication type. The quality of the evidence for the generic adverse event outcomes according to GRADE ranged from very low to moderate, with risk of bias and imprecision being identified for the following generic adverse event outcomes: any adverse event, any serious adverse event, and withdrawals due to adverse events. A GRADE assessment of the quality of the evidence for specific adverse events led to a downgrading to very low- to moderate-quality evidence due to risk of bias, indirectness, and imprecision.We calculated the equivalent milligrams of morphine per 24 hours for each opioid studied (buprenorphine, codeine, dextropropoxyphene, dihydrocodeine, fentanyl, hydromorphone, levorphanol, methadone, morphine, oxycodone, oxymorphone, tapentadol, tilidine, and tramadol). In the 14 Cochrane Reviews providing unique quantitative data, there were 61 studies with a total of 18,679 randomised participants; 12 of these studies had a cross-over design with two to four arms and a total of 796 participants. Based on the 14 selected Cochrane Reviews, there was a significantly increased risk of experiencing any adverse event with opioids compared to placebo (risk ratio (RR) 1.42, 95% confidence interval (CI) 1.22 to 1.66) as well as with opioids compared to a non-opioid active pharmacological comparator, with a similar risk ratio (RR 1.21, 95% CI 1.10 to 1.33). There was also a significantly increased risk of experiencing a serious adverse event with opioids compared to placebo (RR 2.75, 95% CI 2.06 to 3.67). Furthermore, we found significantly increased risk ratios with opioids compared to placebo for a number of specific adverse events: constipation, dizziness, drowsiness, fatigue, hot flushes, increased sweating, nausea, pruritus, and vomiting.There was no data on any of the following prespecified adverse events of interest in any of the included reviews in this overview of Cochrane Reviews: addiction, cognitive dysfunction, depressive symptoms or mood disturbances, hypogonadism or other endocrine dysfunction, respiratory depression, sexual dysfunction, and sleep apnoea or sleep-disordered breathing. We found no data for adverse events analysed by sex or ethnicity.

AUTHORS' CONCLUSIONS: A number of adverse events, including serious adverse events, are associated with the medium- and long-term use of opioids for CNCP. The absolute event rate for any adverse event with opioids in trials using a placebo as comparison was 78%, with an absolute event rate of 7.5% for any serious adverse event. Based on the adverse events identified, clinically relevant benefit would need to be clearly demonstrated before long-term use could be considered in people with CNCP in clinical practice. A number of adverse events that we would have expected to occur with opioid use were not reported in the included Cochrane Reviews. Going forward, we recommend more rigorous identification and reporting of all adverse events in randomised controlled trials and systematic reviews on opioid therapy. The absence of data for many adverse events represents a serious limitation of the evidence on opioids. We also recommend extending study follow-up, as a latency of onset may exist for some adverse events.

Clinical Comments

Family Medicine (FM)/General Practice (GP)

Nothing new here. Opioids are greatly problematic for non-cancer chronic pain, a point that has been repeatedly documented and discussed lately.

FM/GP/Mental Health

Very timely review that emphasizes the risk of chronic use of opioids and also highlights the absence of data about many significant side effects. It rightfully emphasizes the uncertainty of benefit of chronic use. Very sobering!

General Internal Medicine-Primary Care(US)

We know there are adverse events associated with long-term use of opiates, but it is good to have a Cochrane Review to carefully evaluate these events.

Internal Medicine

Clarifies both what is known and the high priority 'need to study' ADRs.


Bottom line: whenever possible try to avoid long-term use of opioids for chronic non-cancer pain. The absolute event rate for serious adverse events of 7.5% is concerning but not terribly surprising. Hopefully this review and other papers will help to turn the tide away from chronic opioid use given the devastating consequences of the ongoing opioid crisis.

Public Health

The article explores the evidence around the side effects of opioids. The ongoing struggle with) opioid epidemic makes the timing of this article relevant, though, it adds little new information to the knowledge about opioids.

Public Health

This is a well done overview. The information on the overall rate of increased serious adverse events will be very helpful when counseling patients. It would be ideal if there were data on some of the other significant AEs, like addiction, overdose, but those data are not available at this time.

Public Health

This is a very timely review of adverse effects of opioids which further documents that adverse effects are frequent when opioids are used for non-cancer pain. It is even more concerning that these studies didn't report rates of addiction, cognitive dysfunction, depressive symptoms or mood disturbances, hypogonadism or other endocrine dysfunction, respiratory depression, sexual dysfunction, and sleep apnea or sleep-disordered breathing. Future studies should report these adverse events in light of the current opioid crisis. The risks of using opioids in the treatment of non-cancer pain are probably underappreciated.

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