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Acute Pain | Chronic Pain | General

Analgesic efficacy of peripheral opioids

Clinical bottom line:

There is no evidence for the efficacy of peripheral opioids either intraoperatively or postoperatively. Trials of a higher quality are needed to provide a definitive answer.

Peripheral opioids in regional analgesia and postoperative pain relief

Opioids are injected close to the nerve trunk or nerve endings in an effort to improve regional anaesthesia and postoperative analgesia. The biological basis for this intervention is the presence of opioid receptors and their endogenous ligands in the peripheral nervous system, and their effect on modulation of inflammatory pain. It is important to establish firstly, whether injected opioids in combination with local anaesthetics improve quality and duration of a sensory block, and secondly, whether doses of local anaesthetic may be reduced. Decreased postoperative pain intensity would demonstrate that opioids have a peripheral action.

Systematic review

PR Picard, MR Tramèr, HJ McQuay and RA Moore. Analgesic efficacy of peripheral opioids (all except intra-articular): A qualitative systematic review of randomised controlled trials. Pain. 1997; 72:309-318.

Inclusion criteria were full journal publication of randomised controlled trials of peripheral opioids; control groups as listed above; group size 10. Intra-articular opioids were not considered as they have been reviewed elsewhere.

Statistically significant data from the original trials were extracted. These findings were then assessed for clinical relevance by consensus, and the consensus agreement was compared with the original authors' conclusion of efficacy.


Experimental pain (4 trials)

Two of two morphine trials (perineural and subcutaneous) showed a beneficial effect. Two of two fentanyl trials (i.e. added to local anaesthetic in a Bier's block) did not demonstrate an effect. In all cases clinical relevance was judged unclear, and findings were therefore excluded from estimates of overall efficacy.

Bier's block (4 trials)

Two fentanyl trials were examined. Although one reported an effect, in two of two cases reviewers decided trials were not clinically significant or there was no significant difference. Similarly of the two morphine trials, one reported an effect. Two of two were regarded as having no clinical significance, or no significant difference.

Other peripheral sites (5 trials)

All trials used morphine. Four of five trials demonstrated no effect (applied to tooth socket, wound, or intraperitoneal / intrapleural block). One of five trials demonstrated an effect with 20 mg given intrapleurally vs. intravenous morphine. Reviewers rated this effect to be of little clinical relevance due to the high morphine dose.

Perineural (3 trials)

Three of three trials reported no significant difference between opioid and control.

Brachial plexus (10 trials)

Opioids were given by interscalene (1 trial), supraclavicular (2 trials) or axillary (7 trials) approaches to the brachial plexus sheath. One of three morphine trials reported an effect, which the reviewers regarded as of no clinical relevance. Two of four fentanyl trials reported an effect, but both were regarded as having no clinical relevance by the reviewers. In one trial Alfentanil was associated with increased duration of sensory and motor block after surgery, but reviewers regarded this as having no clinical relevance. In one trial butorphanol was associated with an effect, which was regarded as having no clinical significance by reviewers. In one trial buprenorphine improved postoperative analgesia compared with morphine. However there were dosing and placebo problems with this study.

Conclusion: of 26 trials, 14 were unequivocally negative. 12 reported at least one statistically significant result in favour of the peripheral opioid. Of these 12, two were in experimental pain (and possibly not applicable to clinical practice), two were regarded by original authors as clinically relevant. Of the eight remaining positive trials, the reviewers did not regard any as being clinically relevant. Reviewers suggest that the negative conclusions drawn from trial may represent lack of evidence rather than efficacy. Most trials included in the review did not demonstrate internal sensitivity and adequate blinding, and had low quality scores in general. Trials with high quality scores could not show any difference between peripheral opioids and control.

Adverse effects

No adverse effects attributable to the route of administration were reported.

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