We read with interest the article by Akural and collegues,1 entitled ‘Peritonsillar morphine infiltration to prevent early postoperative pain after tonsillectomy: A randomised controlled trial’, published in the European Journal of Anaesthesiology. They conducted a randomised controlled study to evaluate the effectiveness of peritonsillar infiltration of morphine in attenuating early postoperative pain after tonsillectomy in adult patients. They found that the local infiltration of 4 mg morphine at the end of the tonsillectomy had no effect on the severity of pain during the early and long-term postoperative follow-up on the injected side.1
Akural et al.1 provided several hypotheses to explain their findings. The first hypothesis proposed was that peripheral infiltration of 4 mg morphine may have affected both sides rather than the selected side with a possible central effect related to systemic absorption. The second hypothesis proposed was that the perioperative and immediate postoperative use of fentanyl and systematically absorbed morphine may have disguised the analgesic effect of the peripheral morphine.1
We wonder whether morphine-6-glucuronide (M6G) would be a better agent to conduct such an investigation. Previously, Klimas and Mikus2 revealed that when administering morphine to patients, the analgesic effect was mainly caused by M6G instead of morphine itself, irrespective of the route of administration, that is, M6G is responsible for the primary analgesic effect after morphine administration. Further, another benefit of using M6G is that M6G is considered peripherally restricted. In experimental human pain models, administration of the peripherally restricted opioid agonists M6G reduced hyperalgesia induced by freeze lesions and excessive muscle contraction, which was verified to be via peripheral action related to the absence of characteristic central nervous system effects.3
Moreover, we wonder if utilising oxycodone instead of morphine would have affected the results. It has been previously shown that κ-opioid receptor agonists, but not μ-opioid receptor or δ-opioid receptor agonists, significantly attenuated visceral afferent output.4,5 Staahl et al.6 have found that in human volunteers, oxycodone, considered to be both a κ and μ receptor agonist, significantly blocked visceral pain better than morphine, which has little kappa receptor activity.
Olesen and colleagues7 studied the pharmacokinetic and pharmacodynamic profiles of oxycodone in a human experimental pain model of hyperalgesia, utilising a multimodal, multitissue paradigm where pain was assessed from skin (heat), muscle (pressure), and viscera (heat and electricity). They found a measurable effect of oxycodone, compared with a placebo, on all pain measures, and a linear concentration-effect relationship without an effect delay. Olesen et al.7 suggested that it could indicate an initial peripheral analgesic effect of oxycodone.
Recently, Smith and colleagues8 studied the analgesic efficacy and systemic exposure of oxycodone administered topically in a novel tocopheryl phosphate mixture gel formulation, to inflamed hind paws in a rat model of inflammatory pain. They found that oxycodone administered topically or by intraplantar injection produced significant (P < 0.05) analgesia in the inflamed hind paws and the systemic oxycodone exposure was insignificant after topical dosing.8
Lastly, it is well known that opioid antinociception through peripheral opioid receptors relies on peripheral tissue inflammation and injury.9 We wonder why intravenous administration of ketoprofen (100 mg) was still utilised as a routine measure at the end of the operation in a study to investigate peripheral opioid analgesia. Indeed, Akural et al. also hypothesised that the infusion of the nonselective cyclo-oxygenase inhibitor, ketoprofen, might have alleviated the peripheral morphine effect. In summary, the authors should be commended for their insightful and creative work. Future studies with slightly modified methodology might better answer many of these challenging questions.
Acknowledgements relating to this article
Assistance with the letter: none.
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Conflicts of interest: none.
Comment from the editor: Dr Akural did not respond to the editors’ invitation to reply to this letter.
1. Akural EI, Alahuhta S, Ohtonen P, Löppönen H. Peritonsillar morphine infiltration to prevent early postoperative pain after tonsillectomy: a randomised controlled trial. Eur J Anaesthesiol
2. Klimas R, Mikus G. Morphine-6-glucuronide is responsible for the analgesic effect after morphine administration: a quantitative review of morphine, morphine-6-glucuronide, and morphine-3-glucuronide. Br J Anaesth
3. Tegeder I, Meier S, Burian M, et al. Peripheral opioid analgesia in experimental human pain models. Brain
4. Gebhart GF. Peripheral contributions to visceral hyperalgesia. Can J Gastroenterol
5. Su X, Wachtel RE, Gebhart GF. Mechanosensitive potassium channels in rat colon sensory neurons. J Neurophysiol
6. Staahl C, Christrup LL, Andersen SD, et al. A comparative study of oxycodone and morphine in a multimodal, tissue-differentiated experimental pain model. Pain
7. Olesen AE, Upton R, Foster DJ, et al. A pharmacokinetic and pharmacodynamic study of oral oxycodone in a human experimental pain model of hyperalgesia. Clin Pharmacokinet
8. Smith MT, Wyse BD, Edwards SR, et al. Topical application of a novel oxycodone gel formulation (tocopheryl phosphate mixture) in a rat model of peripheral inflammatory pain produces localized pain relief without significant systemic exposure. J Pharm Sci
9. Stein C, Lang LJ. Peripheral mechanisms of opioid analgesia. Curr Opin Pharmacol