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Anesthesia & Analgesia:
doi: 10.1213/ANE.0000000000000304
Editorials: Editorial

Nicotine Is Out: Nicotinic Agonists May Have Utility as Analgesics

Flood, Pamela MD, MA*; Damaj, M. Imad PhD

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From the *Department of Anesthesiology, Stanford University, Palo Alto, California; and Department of Pharmacology, Virginia Commonwealth University, Richmond, Virginia.

Accepted for publication April 9, 2014.

Funding: Departmental.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Pamela Flood, MD, MA, Department of Anesthesiology, Stanford University, 300 Pasteur Dr., Palo Alto, CA 94305. Address e-mail to pamelaflood181@gmail.com.

Opioids, nonsteroidal anti-inflammatory drugs, and regional use of local anesthetic drugs are the current mainstays for the treatment of acute postsurgical and traumatic pain. These treatment modalities have dose-limiting side effects and contraindications that result in a significant number of patients who continue to suffer moderate to severe pain in spite of their use. As such, there has been interest in the identification of pharmaceutical agents that act on different molecular targets so as to potentially relieve pain in an additive or synergistic manner. Nicotine and its congeners have been known to reduce responses to noxious stimuli in experimental animals using a variety of nociceptive tests since the 1930s.1 When nicotine became available as a pharmaceutical agent to facilitate smoking cessation, with convenient forms for administration (gum, transdermal patch, and nasal spray) and accumulated reasonable safety data, it was logical to evaluate its analgesic efficacy in clinical trials.

In this issue of Anesthesia & Analgesia, Mishriky and Habib2 report on a meta-analysis including 9 double-blind randomized trials that evaluated the analgesic efficacy of nicotine for acute postoperative pain. The authors concluded that perioperative nicotine administration was associated with a statistically significant reduction in cumulative opioid consumption and a statistically insignificant reduction in pain scores 24 hours after surgery. Both effects were small. The reduction in opioid rescue was restricted to nonsmokers. The minor reduction in use of rescue opioid was offset by an increase in postoperative nausea and vomiting (PONV).

Meta-analysis of pain trials is complicated by the fact that while pain reduction is the primary goal, ethical practice requires that rescue medication for inadequately treated pain be immediately available. As such, all pain trials have 2 primary outcomes, pain report and use of rescue medication. If the rescue medication was truly immediately available and without side effect, one would expect the pain report always to be equivalent among trials and the treatment effect would only be found in the dose of rescue analgesic. Actual clinical trials are never that clean. Three of the 9 trials included in the study by Mishriky and Habib2 reported lower pain scores in the active group while 2 identified lower rescue medication use. Two of the included trials evaluated PONV as a primary outcome variable, and the pain data were not explicitly provided in the original manuscripts. Although it is difficult to combine these end points, the effect sizes were small in all cases, and the only significant effect shown in the meta-analysis was a reduction in rescue medication of about 5 mg morphine in the first 24 hours after surgery. This small benefit was offset by an increase in nausea and vomiting in most trials involving nonsmokers and dizziness and adverse dreams in those trials that assessed those end points. Given that patients rate PONV a greater concern than pain,3 the perioperative use of nicotine is probably a nonviable treatment option. However, it is not time to throw the baby out with the bath water.

Nicotine is the prototypical nicotinic agonist that activates and desensitizes most of the large variety of pentametric nicotinic receptors subtypes composed of differing combinations of 10 α (ligand binding) and 3 β subunits in the central and peripheral nervous systems and in nonneuronal tissues. Nicotinic receptors play a major role as presynaptic modulators of both inhibitory and excitatory transmission and are well represented in classical pain pathways.4 The nicotinic subtypes, however, are not distributed in a homogenous manner in these various peripheral and central regions. The idea that subtype-selective and/or peripherally restricted nicotinic ligands might provide a profile that includes potent and effective analgesia with minimal side effects has driven research within the pharmaceutical industry for years. Epibatidine, a naturally occurring substance in the skin of an Ecuadoran poison frog that has 100 times more potent antinociceptive activity than morphine, served as a stimulus for the development of many new subtype-selective nicotinic agonists.5 Unfortunately, to date, all tests on the analgesic utility of α4β2 nicotinic agonists, the main receptor subtype, have been restricted by dose-limiting side effects.6 Like nicotine for postoperative pain, one α4β2 selective nicotinic agonist has shown efficacy in treating diabetic neuropathic pain in a phase 2 trial but was plagued by side effects including dizziness, nausea, vomiting, and unpleasant dreams.7 Recent animal studies suggest that α7 nicotinic receptors may represent a new target for analgesic and anti-inflammatory agents.8 Peripherally restricted α7 selective agonists have efficacy in inflammatory pain and seem to be devoid of the above side effects in animal models. Finally, positive allosteric modulators for α4β2 and α7 nicotinic receptor subtypes, which either enhance receptor function and/or reduce desensitization, have shown some promise particularly in combination with other nicotinic modulators in animal models of chronic pain.9,10

Mishriky and Habib2 have synthesized the information gleaned from many trials on nicotine as an adjuvant for the management of postoperative pain. They found that the small benefit was offset by negative side effects. However, studies on subtype-selective nicotinic agonists and modulators suggest that the dose-limiting side effects found are mediated by direct activation of the α4β2 subtype nicotinic receptor in the central nervous system. As such, while nicotine is not useful in the perioperative period, subtype- selective nicotinic modulators continue to offer potential promise to the armamentarium against acute and chronic pain. E

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Dr. Pamela Flood is the wife of Dr. Steven Shafer, Editor-in-Chief of Anesthesia & Analgesia. This manuscript was handled by James G. Bovill, Guest Editor-in-Chief and Dr. Shafer was not involved in any way with the editorial process or decision.

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Name: Pamela Flood, MD, MA.

Contribution: This author helped write the manuscript.

Attestation: Pamela Flood approved the final manuscript.

Name: M. Imad Damaj, PhD.

Contribution: This author helped write the manuscript.

Attestation: M. Imad Damaj approved the final manuscript.

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