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EDITORIAL

Nicotine and Postoperative Management of Pain

From the Division of Clinical Pharmacology and Experimental Therapeutics, Medical Service, San Francisco General Hospital Medical Center, the Departments of Medicine and Biopharmaceutical Sciences University of California, San Francisco, California.

Address correspondence and reprint requests to Neal L. Benowitz, MD, Chief, Division of Clinical Pharmacology and Experimental Therapeutics, University of California, San Francisco, Box 1220, San Francisco, CA 94143-1220. Address e-mail to NBenowitz{at}MedSFGH.ucsf.edu.

In 1931, Davis et al. observed that injection of nicotine abolished the respiratory response to gall bladder distention, a model for visceral pain, in cats.1 In 1974, Daly et al. discovered that alkaloids extracted from the skin of the frog Epipedobates tricolor produced a Straub tail response in mice (a rigid, erect, S-shaped tail) that was similar to that produced by opioids.2 The active constituent of the frog skin extract was determined to be epibatidine, later found to be a nicotinic cholinergic receptor (nAChR) agonist with an analgesic potency 100 times that of morphine.3 Although epibatidine is a potent analgesic, it also has severe toxic effects that preclude its use as an analgesic. Later studies demonstrated an antinociceptive effect of nicotine in rodents, and showed that smoking tobacco cigarettes decreased sensitivity to pain, at least in some pain tests.4,5

Nicotine acts on nicotinic cholinergic receptors, which are found in the central nervous system, autonomic ganglia, the neuromuscular junction, as well as in several non-neuronal tissues. The nicotinic cholinergic receptor is a ligand-gated channel comprised of five transmembrane spanning subunits. Neuronal nAChRs are comprised of and β subunits. The most widely distributed receptor subtypes in the brain and the receptor subtype believed to be most involved in nicotinic dependence is the 4 β2* receptor. (The asterisk indicates that other receptor subunits may also be included.) The 7 subunit forms homomeric receptors that are believed to be involved in rapid synaptic transmission.

The mechanism of nicotine-mediated cholinergic analgesia appears to involve several pathways. Nicotine acts on nAChRs in both the brain and the spinal cord to activate spinal cord descending inhibitory pain pathways.6 Nicotine-mediated analgesia is thought to involve, at least in part, local release of norepinephrine, with activation of 2-adrenergic receptors. Morphine itself works, at least in part, by releasing acetylcholine, which acts on nAChRs. Nicotine may also produce analgesia by release of endogenous opioids. Nicotine-induced antinociception is reduced in µ opioid receptor knockout mice.7,8 Furthermore, nicotine has antiinflammatory actions that could reduce pain.9,10

Several papers in this issue of the journal further elucidate the mechanism of action of nicotine to produce analgesia. Epibatidine was determined to be a high affinity agonist at the 4 β2 and 7 nAChRs.3 Rowley et al. provide confirmatory evidence that 4 β2 nicotinic agonists have antinociceptive effects in a mouse postoperative pain model, and showed that 7 nicotinic agonists also have some antinociceptive effects.11 The Rowley and Flood study confirms that nicotine facilitates norephinephrine release in mouse spinal cord, and shows that isoflurane inhibits this effect of nicotine.12 It is speculated that the hyperalgesia that occurs with isoflurane anesthesia is due to inhibition of norepinephrine release in spinal pathways.

Given that the analgesic effects of nicotine have been demonstrated in many years of prior research, it is reasonable to consider the possibility that nicotine might be useful in managing postoperative pain. Postoperative pain remains a problem in many patients, and treatment with high doses of opiates required to control postoperative pain is often associated with adverse effects. There is a need for medications that augment postoperative analgesia to allow better pain control with lower doses of opiates.

Several clinical studies on the potential utility of nicotine as an adjunct to postoperative pain management have been published. The first study, published by Flood an Daniel in 2004, found that women undergoing transabdominal uterine surgery (myectomy or hysterectomy) experienced enhanced postoperative analgesia after administration of nicotine nasal spray.13 Nicotine nasal spray, in a dose of 3 mg, administered at the completion of surgery, lowered pain self-assessment scores and reduced the dose of morphine taken by patient-controlled analgesia (PCA) for 60 min after surgery, compared with placebo treatment. Pain scores were significantly lower for a full 24 h after nicotine dosing, which is surprising since nicotine has a half-life of 2 h. When administered as a single nasal dose, nicotine levels would be expected to dissipate quickly and to reach extremely low levels within a few hours after dosing.

Three follow-up studies are now published in this issue of the journal. Hong et al. studied 40 nonsmokers who underwent pelvic or abdominal surgery.14 Immediately before surgery, patients underwent treatment with placebo, 5, 10, or 15 mg/16 h nicotine patches. Patches were removed at bedtime on the day of surgery. Nicotine treatment resulted in lower pain scores for the first hour after surgery and then for the next 4 days at home. There was a trend for use of lower amounts of morphine by PCA. However, there was no evidence of a nicotine dose–response relationship; pain relief with the 5 mg dose was similar to that seen with higher doses. Transdermal nicotine slightly increased the incidence of nausea and vomiting at the two higher nicotine doses. Habib et al. reported on 90 nonsmoking men undergoing retropubic prostastectomy who were treated with transdermal nicotine 7 mg or placebo 30–60 min before surgery.15 Patches were left in place for 24 h. There was no significant difference in self-reported pain score, but patients who received nicotine used significantly less morphine via PCA at 6 and 24 h, compared with the placebo group. Plasma nicotine concentrations measured at 6, 12, and 24 h after surgery were negatively correlated with morphine consumption. This finding of a significant concentration–response relationship supports that this is a true biological effect. There was a trend toward more vomiting in the nicotine-treated group.

In contrast to the Flood and Daniel, Hong et al., and Habib et al. studies mentioned above, Turan et al., who studied 97 women undergoing abdominal hysterectomy, found that pretreatment with transdermal nicotine 21 mg/24 h patches, beginning 1 h before induction of anesthesia and continuing for 2 days after surgery,16 provided no benefit with respect to postoperative pain. There was no difference between nicotine and placebo patch-treated patients in self-reported pain score or in morphine requirement, and no difference in the incidence of nausea or vomiting. Sixty percent of subjects in this trial were smokers. A subgroup analysis comparing smokers versus nonsmokers found no difference in response.

The explanation for the failure of the Turan et al. trial to find a postoperative analgesic effect of nicotine in contrast to the findings of the other authors may have been related to dosing and subject selection issues and to the development of tolerance. The trial report by Turan et al. differed from the other trials in two important ways. First, the Turan et al. trial included smokers, whereas the others included only nonsmokers. Second, the dose of nicotine was higher in the Turan et al. trial than in the other trials. As mentioned by Turan et al., the development of profound tolerance to many effects of nicotine is well known. Tolerance might be expected to be more prominent in individuals who received higher doses of nicotine and to be more prominent in smokers. Arguing against the importance of smoking status was the observation by Turan et al. that even in the subgroup of nonsmokers, there was no benefit of transdermal nicotine.

Nicotine desensitizes nAChR more or less completely depending on the receptor subtype. Persistence of higher levels of nicotine in the body during higher dose patch application could have resulted in receptor occupation and desensitization such as to preclude a nicotinic action to promote analgesia. In relation to addiction, some researchers have speculated that nicotine derived from regular cigarette smoking results in occupation and desensitization of nAChRs throughout the day, and that the desensitization of nicotinic receptors might in itself be an important mechanism of reinforcement that maintains addiction in smokers.17

As mentioned previously, Flood and Daniel found a prolonged analgesic effect from nicotine that was dosed only once at the end of surgery. This is in the face of a half-life of 2 h, predicting that nicotine would be almost completely eliminated from the body within 8–10 h.18 One explanation for a prolonged analgesic effect of nasal spray might be a lack of desensitization of nAChRs at very low nicotine concentrations. It is possible that nicotine in very low concentrations might provide effective analgesia without desensitizing the relevant receptors. Maio et al. conducted a series of studies examining the effects of nicotine on bradykinin-induced extravasation in rats, which was used as a model of inflammation.9 Nicotine was shown to have both anti- and proinflammatory effects, depending on the dose. Some effects of nicotine were seen at subnanomolar concentrations, which are well below those that are seen with tobacco use.19 Conceivably, the effects of nicotine on spinal pain transmission might be seen at similarly low concentrations of nicotine that might be seen many hours after nasal nicotine administration, such as in the clinical trial reported by Flood and Daniel. Thus, it is important to conduct follow-up clinical research on nicotine for postoperative analgesia with systematic exploration of the nicotine analgesia dose–response, including consideration of effects of rapidity of dose delivery, smoking status of patients, and the sex of the patients.

A critical issue in considering nicotine use postoperatively is whether nicotine is safe. All of the published studies suggest that nicotine used as an adjunct to postoperative analgesia is relatively safe. Nicotine did increase the incidence of nausea and vomiting in some studies, but these adverse events appeared to be mild. No adverse cardiovascular effects were reported. There is some concern that nicotine’s vasoconstricting activities can impair wound healing, but since nicotine dosing would most likely be for 24 h or less, this is not likely to have an adverse effect on recovery from surgery.

In conclusion, several small clinical trials indicate that nicotine nasal spray or transdermal nicotine in low doses can reduce postoperative pain and/or reduce postoperative opiate requirements. The one study that did not find the beneficial effect studied a mixture of smokers and nonsmokers and administered relatively high doses of sustained release, transdermal nicotine. The failure of the latter study to show benefit might be related to the complexity of the pharmacodynamic actions of nicotine, including development of tolerance and its nonlinear dose–response. Further research is needed comparing different dosing systems (that is, rapid vs slow delivery) and exploring different doses, including very low doses that might produce analgesia without the development of tolerance. One cannot recommend routine clinical use of nicotine for postoperative analgesia at this time, but recent findings are promising and indicate that larger clinical trials are warranted.

	Footnotes

 
Accepted for publication May 21, 2008.

Supported, in part, by DA02277 from the National Institute on Drug Abuse.

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