Authors of opioid pain study respond to critics

5 minute read

The study found that opioids were no better than placebo for people with acute low back or neck pain, and could cause worse outcomes in the long term.

Two weeks ago, The Lancet published the findings of the placebo-controlled OPAL trial.

The trial found evidence that a commonly used opioid, oxycodone, was not more effective than placebo for people with acute, non-specific low back and/or neck pain of moderate to severe intensity and may cause worse outcomes in the long term.

Current clinical guidelines for acute low back pain recommend that opioids be considered only when other treatments are not appropriate or have failed. However, the findings of the OPAL trial challenge use for this condition.

The OPAL trial recruited close to 350 people with acute low back pain and/or neck pain who presented to a general practitioner or the hospital emergency department. Those who presented to the emergency department were seen by a rheumatologist either in emergency, or by referral in an outpatient clinic.

Participants were randomly allocated to receive either an opioid or matching placebo, to be taken for up to six weeks. In addition, all participants received guideline care (reassurance of a positive prognosis, advice to stay active and to avoid bed rest, and if required, other guideline-recommended treatments including non-opioid analgesics) from their doctor and were followed up for up to one year.

At six weeks (the primary time point), there was no difference in pain intensity between the opioid and placebo groups. Taking opioids also did not improve other clinical outcomes, such as physical function, quality of life or recovery time. At one year, people in opioid group had slightly worse pain and a higher risk of opioid misuse.

The medicine used in the OPAL trial was a commonly used oral modified-release formulation of oxycodone/naloxone. The recommended regimen was oxycodone 5mg every 12 hours, with titrating as necessary, without exceeding 20mg total per day. Trial doctors were able to individualise the prescription to suit the patient. In the study, the mean prescribed dose was approximately oxycodone 10mg total daily.

The choice of study medicine was based on a few factors. A modified-release opioid formulation allowed participants to take tablets twice per day rather than four to six times, which may increase adherence. The co-administration of oral naloxone reduces the risk of opioid-induced constipation, which helped to keep participants comfortable and reduced the likelihood of them becoming unblinded due to this obvious side effect.

The recommend treatment regimen was that the study medicine be used until recovery, or for a maximum of six weeks. The majority of OPAL participants used the trial medicine for two weeks, ceasing for various reasons including having recovered, lack of effect, or intolerance. There was no difference between groups in the number ceasing the study medication at any timepoint.

We note some commentary that immediate-release formulations may have provided a different result to OPAL. However, regular doses of modified-release opioids will have achieved similar concentrations compared to immediate-release within the first day or two. This is important as our treatment period was weeks, not hours. The benefits of the modified-release oxycodone/naloxone formulation (better adherence, less constipation, maintaining blinding) outweighed the downside of not being able to titrate the dose as quickly compared to an immediate-release formulation.

Some have commented that we may have missed a treatment effect as our primary time point of six weeks might be too long of a timepoint. However, we also measured pain intensity on a scale of 0-10 daily for the entire treatment period, plus six more weeks (12 weeks in total). These daily pain scores suggest a trend towards faster recovery (defined as achieving pain scores of 0-1/10 for 7 days) in the placebo group in the first 14 days.

It is also important to note that the OPAL trial applies to people with acute low back pain and neck pain. For those with chronic pain who are on long-term opioid therapy, reducing opioid can be challenging, and one that needs collaboration between the patient and clinicians to avoid causing unintended harms. The recent NHMRC-endorsed guideline provides recommendations on opioid deprescribing.

Opioid overuse remains a challenge in Australia and globally. All can agree that opioids should not be used in situations where benefits do not outweigh the harms.

The OPAL trial has provided evidence to show that this is the case for people with non-specific acute low back pain and neck pain. Treatment for non-specific acute low back pain should focus on advice of staying active and avoiding bed rest, reassurance of a favourable prognosis and, if required, anti-inflammatories drugs for pain relief to allow the patient to stay active.

For presentations of acute spinal pain to the emergency department, there is interest in rapid pain control, with the goal being pain control within 2-4 hours of presentation. As our first follow-up was at day one, the OPAL trial cannot guide clinicians on this issue.

There are very few placebo-controlled trials that have evaluated pain medicines for spinal pain in the ED setting and so the optimal analgesic strategy in the ED context is unclear. A recent systematic review found some evidence that opioids are not superior to other analgesics such as anti-inflammatories within in the ED in time periods of 30 minutes to 2 hours.

With ED colleagues, we are planning a trial to fill that critical evidence gap.

The Lancet 2023, 28 June

This article was written by Dr Caitlin MP Jones, Professor Ric Day, Professor Christine Lin, Professor Andrew McLachlan and Professor Christopher Maher who are among the co-authors of the OPAL study.

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