Education  |   October 2010
Smoking and Pain: Pathophysiology and Clinical Implications
Author Affiliations & Notes
  • Yu Shi, M.D., M.P.H.
  • Toby N. Weingarten, M.D.
  • Carlos B. Mantilla, M.D., Ph.D.
  • W. Michael Hooten, M.D.
  • David O. Warner, M.D.
  • * Research Fellow, † Assistant Professor of Anesthesiology, ‡ Associate Professor of Anesthesiology and Physiology, § Professor of Anesthesiology, Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota.
Article Information
Education / Pain Medicine
Education   |   October 2010
Smoking and Pain: Pathophysiology and Clinical Implications
Anesthesiology 10 2010, Vol.113, 977-992. doi:10.1097/ALN.0b013e3181ebdaf9
Anesthesiology 10 2010, Vol.113, 977-992. doi:10.1097/ALN.0b013e3181ebdaf9
APPROXIMATELY 1 in 5 Americans smoke cigarettes,1 and at least 1 in 10 nonsmokers is exposed to secondhand smoke at home.2 Thus a large population is chronically exposed to nicotine and the other constituents of cigarette smoke. The implications of cigarette smoking to the practice of anesthesiology and pain medicine are complex and not well understood. Cigarette smoke contains thousands of compounds, with many of them producing significant physiologic effects. However, cigarettes serve primarily as a device to deliver nicotine. Nicotine has analgesic properties, first observed in feline visceral pain models3 and since then replicated in numerous animal and human studies.4–13 Its analgesic effects likely result from effects at both central and peripheral nicotine acetylcholine receptors (nAChRs).8,14,15 Other nAChR ligands also have potent analgesic effects.16–20 On the other hand, clinical evidence suggests that smokers are at increased risk of developing back pain and other chronic pain disorders.21–32 Furthermore, comparisons between smokers and nonsmokers with chronic pain disorders have repeatedly demonstrated that smokers have higher pain intensity scores that have greater impact on occupational and social function.33–37 This apparent paradox is not only of considerable scientific interest, but also has clinical relevance in caring for smokers in the perioperative period and smokers with chronic painful conditions.
This paper will review how acute and chronic exposure to nicotine, which is currently delivered most commonly via  cigarette smoke, affects acute and chronic painful conditions. We first review briefly the relevant pharmacology of nicotine and other ligands at the nAChR as related to pain, explore the association of cigarette smoking with chronic painful conditions and potential mechanisms to explain this association, and examine clinical implications for those who care for smokers with pain. We focus on cigarette smoking, as most of the relevant literature in humans concerns this method of nicotine delivery, recognizing that other forms of tobacco use (e.g.  , smokeless tobacco) may have similar (or different) effects on pain.
Pharmacology of Nicotine Acetylcholine Receptors
The alkaloid nicotine exhibits its pharmacological effects by interacting with ion channels of the nAChR family. The nAChR consists of a pentameric complex of transmembrane proteins that form a central pore permeable to Na+, Ca2+, and K+ions.38 The structure of the muscle-type of nAChR has been characterized with high resolution and has served for modeling ligand binding sites of neuronal nAChRs.39 Muscle-type nAChRs consist of (α1)2β1Δϵ (adult) or (α1)2β1Δγ (fetal) forms, with α1, β1, γ, Δ, and ϵ subunits being expressed only in skeletal muscle. Neuronal nAChRs are composed of different combinations of α (α2–α10) and non-α (β2–β4) subunits.40 The endogenous ligand ACh binds at the interface between an α subunit and neighboring subunits, and thus, nAChRs will differ in their ACh binding depending on their subunit composition. Whereas α4β2* heteromers (where * denotes possible additional subunits) will have two binding sites for agonists and competitive antagonists, homopentameric α7 nAChRs will have up to five binding sites.38,41 
The family of nAChRs shows wide distribution in the central and peripheral nervous systems and is involved in numerous processes, including arousal, sleep, anxiety, cognition, and pain.38 In the central nervous system, the homomeric α7 (α-bungarotoxin-sensitive) and the heteromeric α4β2* (α-bungarotoxin-insensitive) receptors predominate.42–44 The α4β2* receptors are present in the spinal cord dorsal horn, thalamus, and other brain regions associated with nociceptive transmission and modulation.45,46 The α9α10 nAChR (also α-bungarotoxin-sensitive) is not present in the central nervous system, but is found in the dorsal root ganglia, leukocytes, vestibular and cochlear mechanosensory hair cells, and other tissues47–49 (fig. 1).
Fig. 1.  Schematic representation of the potential sites of analgesic action of nicotine. In the central nervous system, there is widespread distribution of homomeric α7 and heteromeric α4β2* nicotinic acethylcholine receptors (nAChR), including regions associated with pain transmission such as the dorsal horn, locus ceruleus, and thalamus. The α9α10 nAChR is present in dorsal root ganglia. Many anesthetics also modulate or inhibit nAChR function. Activation of supraspinal and spinal nAChR results in opioid and norepinephrine (NEpi) release, which can reduce descending facilitatory pain pathways (green  ) and enhance descending inhibitory pain pathways (red  ), resulting in reduced transmission of nociceptive input (blue  ).
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Fig. 1.  Schematic representation of the potential sites of analgesic action of nicotine. In the central nervous system, there is widespread distribution of homomeric α7 and heteromeric α4β2* nicotinic acethylcholine receptors (nAChR), including regions associated with pain transmission such as the dorsal horn, locus ceruleus, and thalamus. The α9α10 nAChR is present in dorsal root ganglia. Many anesthetics also modulate or inhibit nAChR function. Activation of supraspinal and spinal nAChR results in opioid and norepinephrine (NEpi) release, which can reduce descending facilitatory pain pathways (green  ) and enhance descending inhibitory pain pathways (red  ), resulting in reduced transmission of nociceptive input (blue  ).
Activation of postsynaptic nAChRs exerts direct excitatory neuronal effects via  their cationic channel. Presynaptically, nAChR activation can potentiate the release of other neurotransmitters, including dopamine, γ-aminobutyric acid, glutamate, serotonin, histamine, and norepinephrine.38,40 Subsequent neurotransmitter release contributes to the complex effects of nicotine and other nAChR ligands in different neuronal pathways. Neuronal nAChRs have multiple ligands and modulators, including neurosteroids, local anesthetics, phencyclidine, and MK-801.50 Volatile anesthetics and ketamine are potent inhibitors of α4β2 and α3β4 nAChRs at clinically relevant doses.51 Particular nAChR subunits exhibit varying selectivity to the different ligands, thus contributing to complex pharmacological profiles. In addition, the kinetics of nAChR channel opening may vary. Whereas nAChRs display fast opening of their cation channel upon ACh binding in response to the usual high-concentration, brief exposure to released ACh, when they are exposed chronically to low agonist concentrations, there is a reduction in channel opening rates, resulting in a closed, desensitized state.38 During prolonged exposure to nAChR ligands, changes in receptor number or function may occur. For instance, prolonged exposure of animals to low levels of nicotine typically seen in chronic smokers results in an up to 2-fold up-regulation of nAChR expression in the brain.52,53 Human studies using positron emission tomography also show that smokers have greater densities of high-affinity AChRs in several brain regions compared with nonsmokers and ex-smokers.54 These aspects of nAChR pharmacology are clearly important in drug development. In the following section, nAChR ligands investigated in animal models and human studies in regard to pain behaviors and perception are considered.
Animal Studies
In 1932, Davis et al.  reported that systemic nicotine attenuated pain behaviors in an experimental visceral pain model of gallbladder distention in cats.3 Subsequent work demonstrated that although activation of peripheral nAChRs produces pain,55,56 acute exposure to systemic nicotine has consistent antinociceptive effects in rodents as measured in tail flick and hot plate models.4–8,57,58 For example, Tripathi demonstrated that subcutaneous administration of nicotine produced a significant increase in tail flick test thresholds in both male rats (1 mg/kg) and mice (3 mg/kg).8 Different pain models may involve different neural pathways,59 and nicotine does not consistently have similar effects in thermal paw withdrawal or mechanical pain models (Von Frey tests),57,58 although such effects are present in a mouse model of postoperative pain.60 The antinociceptive properties of nicotine are also evident when nicotine is administered via  cigarette smoke.57,61 
Several possible mechanisms may be involved in the antinociceptive properties of systemic nicotine. Withdrawal reflexes are spinally mediated but also modulated supraspinally,62 so that activation of nAChRs at both spinal and supraspinal sites may be involved; studies using systemic treatments cannot elucidate the effect site. A supraspinal site for the antinociceptive effects of nicotine is suggested by the involvement of opioid and serotonergic systems (fig. 1).
Several lines of evidence suggest that the antinociceptive properties of nicotine are at least partly mediated by the endogenous opioid system. First, the antinociceptive effects of nicotine on the tail flick test are blocked by the administration of either the centrally acting nicotinic antagonist mecamylamine or the opioid antagonist naltrexone.61 Berrendero et al.  demonstrated that nicotine antinociception is attenuated in μ-opioid receptor knock-out mice and in mice that lack the preproenkephalin gene.63,64 Second, centrally administered nicotine augments antinociception resulting from μ-opioid receptor activation in murine models.65,66 Nicotine administration also produces an up-regulation of μ-opioid receptors in the striatum of rats.67 However, other studies reported that μ-opioid receptor antagonism only incompletely attenuates61,68 or does not reduce nicotine-induced antinociception.8,69,70 
The serotonergic system likely also plays an important role in modulating nicotine-induced antinociception.71–74 The antinociceptive effects of nicotine are reduced in a dose-dependent manner by serotonergic 5HT1Aagonists such as 8-OH-DPAT (8-hydroxy- 2-(di-n-propylamino)tetraline) and buspirone.71 Inhibition of serotonin biosynthesis and subsequent depletion of available serotonin stores (e.g.  , using parachlorophenylalanine) enhances the antinociceptive effects of nicotine.72 However, the exact mechanisms and pathways underlying serotonergic modulation of the antinociception induced by acute exposure to nicotine are not clear.
Chronic nicotine exposure results in tolerance to nicotine-induced antinociception.57,61,75 In rats, continuous administration of nicotine produces antinociception for only a short period of time after initiation of administration.58,68,76 Chronic exposure causes widespread adaptive changes in the endogenous opioid system which may affect processing of nociceptive stimuli in general.67,75,77,78 Compared with nicotine-naïve rats, nicotine-tolerant rats develop greater mechanical hyperalgesia after spinal nerve ligation or sciatic nerve injury.79,80 The increased mechanical hyperalgesia was associated with increased spinal dynorphin levels81 as well as increased production of cytokines centrally and peripherally.79 Thus, when evaluating the behavioral effects of chronic nicotine exposure a complex interplay among receptor desensitization, overexpression, and neural plasticity in associated nociceptive pathways must be considered. Furthermore, nicotine withdrawal was associated with hyperalgesia in nicotine-tolerant rodents,57,82,83 which was reversible by morphine administration.82 
Other Nicotine Acetylcholine Receptor Ligands.
Nicotine may exert analgesic effects via  one or many different nAChR subtypes. Multiple studies have been conducted in an attempt to obtain more selective analgesic compounds. These studies may also help to identify the mechanisms of analgesic action for nAChR ligands.
Agonists of α4β2 Nicotine Acetylcholine Receptors.
The demonstration that the alkaloid isolated from the skin of the Ecuadorian poisonous-arrow frog Epipedobates tricolor  is a potent analgesic prompted considerable research into this and other nicotinic agonists as potentially clinically useful agents.17 Epibatidine has a high affinity for and is a potent agonist of the α4β2 and α7 nAChRs.84,85 Epibatidine has potent analgesic effects in a variety of murine pain models, including the hot plate assay, tail-flick test, and carrageenan pain model.16–18 The analgesic actions of epibatidine are blocked by the centrally acting nAChR antagonist mecamylamine, but not by the peripherally acting antagonist hexamethonium, or naloxone.17,86,87 Importantly, the analgesic properties of epibatidine are not affected by blockade of α-bungarotoxin-sensitive receptors with methyllycaconitine, suggesting that α7 nicotinic receptors are not involved in analgesia.15 The azetidine analog of epibatidine, ABT-594 [(R  )-5-(2-azetidinylmethoxy)-2-chloropyridine] has a similar affinity for the α4β2 nAChRs, but a very low affinity for α7 nAChRs, ganglionic, and muscular nAChRs.19 Accordingly, ABT-594 is a potent oral analgesic in a variety of pain models in rodents and maintains its analgesic effects with repeated dosing.88–90 Like epibatidine, the analgesic actions of ABT-594 are blocked by mecamylamine, but not by hexamethonium or naltrexone.91 Sazetidine-A, a partial agonist of the α4β2 receptor, produces analgesia in a formalin test in rats.20,92 Varenicline, an effective medication for smoking cessation, is a partial agonist at α4β2 and a full agonist at α7 neuronal nAChRs,93 and it has analgesic effects in the rat formalin test.94 
Unfortunately, α4β2 ligands have significant unacceptable side effects. Both epibatidine and ABT-594 show serious side effects at or near doses required for analgesia. Epibatidine produces hypertension, neuromuscular paralysis, seizures, and death in rodents.17,95 Although ABT-594 showed reduced side effects compared with epibatidine in some animal studies,88–90 it produces hypothermia, seizures, and hypertension in rats (like high-dose nicotine), and after repeated exposure rats develop an abstinence syndrome.96 This side effect and toxicity profile has precluded investigation of these agents in human trials.97 As a partial agonist, sazetidine-A administration may be less limited by undesirable effects,20 but further preclinical studies are needed.
Investigation of the mechanism of action of α4β2 agonists suggests that analgesia is mediated predominantly via  a supraspinal effect. Epibatidine administration produces dopamine release from striatal slices, norepinephrine release from the hippocampus and thalamus, and excitatory amino acids from the spinal cord.98,99 Epibatidine activates the nucleus raphe magnus, dorsal raphe, and locus coeruleus, all areas that are involved in the central modulation of pain via  descending inhibitory pathways.45,100,101 The analgesic properties of epibatidine are attenuated by phenoxybenzamine and N  -(2-chloroethyl)-N  -ethyl-2-bromobenzylamine (DSP-4, a neurotoxin that depletes norepinephrine) but not by dopamine antagonists.15,99 
Antagonists of α9 or α10 nAChRs.
Highly selective α9 or α10 nAChR antagonists derived from cone snail toxins have been developed, including Vc1.1, RgIA, and PeIA.102–104 The α-conotoxin Vc1.1 attenuates the increase in axonal excitability of human unmyelinated C-fiber axons produced by nicotine.105 Subcutaneous and intramuscular administration of Vc1.1 produces analgesia in neuropathic pain models in rats that is sustained without signs of tolerance.102,106 Interestingly, administration of Vc1.1 also improves nerve recovery from and attenuates the inflammatory response to nerve injury.102,106 It has been postulated that antagonism of the α9 or α10 nAChRs produces analgesia in part by immunomodulation.107 The exact role, if any, of other nAChR ligands is presently unclear.
Human Studies
Experimental Pain Studies.
Nicotine produces analgesia in human models of experimental pain. In general, nicotine administration via  nasal spray or transdermal patches reduces pain sensitivity in both smokers and nonsmokers.10,108 Smoking a cigarette decreases awareness of and increases tolerance to some experimental pain stimuli,10,12,13 but these effects may involve additional substances in cigarette smoke, as they are attenuated when nicotine-depleted cigarettes are smoked.9,11 
Results from studies with humans are more difficult to interpret than are results from animal studies for several reasons. First, many human studies involve those habituated to cigarette smoke, because nicotine administration to naïve subjects may be associated with unpleasant side effects such as nausea. Beyond the effects of prolonged nicotine exposure on nAChRs, the timing of the experimental nicotine exposure in relation to the last cigarette smoked may be important given the rapid decrease in nicotine levels in the absence of continued smoking (half-life of ∼1 h).109 Second, analgesic effects of nicotine may differ across experimental pain models (table 1). Although nicotine consistently increases pain thresholds in cold pressor tests,9,11,13,110 results are inconsistent with heat108,111,112 or electrical stimulation pain models.10,12,113–115 Finally, the effects of nicotine may depend on sex. Studies of male subjects find that smoking consistently produces analgesia,9,11,13,112 whereas studies with only or mostly females report negative results.113,116 In one study involving both sexes, transdermal nicotine increased pain thresholds to electrical stimulation in males but not females.10 However, two other studies found no sex differences in the effects of smoking on cold pressor pain.13,110 
Table 1.  Effects of Smoking and Nicotine on Experimental Pain in Humans
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Table 1.  Effects of Smoking and Nicotine on Experimental Pain in Humans
As with animal studies, the mechanisms of nicotine analgesia are not completely understood in humans, especially because the range of experimental options is more limited. Nicotine effects on pain responses may represent treatment of nicotine withdrawal rather than direct analgesic effects in studies examining smokers deprived of nicotine.117 However, the antinociceptive effect of nicotine is present in both nicotine-deprived subjects and those who have maintained regular smoking.9,11,108 Nicotine administration in cigarette smoke may also confound interpretation of analgesic effects. Smoking increases blood pressure and heart rate,116 which can reduce pain sensitivity.108,118,119 However, blockade of ß-adrenoreceptors to attenuate sympathetic activation caused by smoking does not affect heat pain sensation,12 although it blunts antinociceptive effects of nicotine in heavy, but not light or moderate, smokers in an electrical stimulation experimental pain model120 (see also discussion in the section “Potential Mechanisms of Chronic Pain in Cigarette Smokers”).
Postoperative Pain.
Several studies have explored the possibility that systemic nicotine could be used to provide postoperative analgesia. In a placebo-controlled trial of nonsmoking female patients undergoing uterine surgery via  a low transverse incision, nicotine enhanced morphine analgesia.121 Patients who received a single 3 mg dose of nicotine nasal spray before emergence from general anesthesia reported lower pain scores during the first hour after surgery, used half the amount of morphine, and reported less pain 24 h after surgery.121 However, another study from this group found that the administration of 3 mg of intranasal nicotine did not reduce analgesic requirements in nonsmoking females undergoing open uterine surgery.122 In the latter study, patients were assigned to a general anesthetic with either isoflurane or propofol and administered nicotine or placebo nasal spray. In both anesthetic groups, nicotine failed to significantly reduce postoperative opioid requirements, although the sample sizes in this study were small. In a study of both male and female nonsmokers, transdermal nicotine patches applied immediately before surgery and removed the night after surgery improved immediate and sustained (5 days) analgesia after abdominal and pelvic procedures, with a ceiling response above the 5 mg/24 h dose.123 In males undergoing radical retropubic prostatectomy, nonsmokers who received a 7 mg/24 h transdermal nicotine patch applied before general anesthesia significantly reduced morphine requirements in the first 24 h postoperatively.124 In contrast, Turan et al.  reported that 21 mg/24 h transdermal nicotine patches did not improve postoperative pain or have opioid-sparing effects in females undergoing abdominal hysterectomy.125 However, 61% of the subjects in this study were smokers and thus chronically exposed to nicotine. In another study, smokers undergoing abdominal or pelvic surgery did not report improved analgesia or reduced opioid consumption with preoperative application of transdermal nicotine in doses from 5 to 15 mg/24 h.126 Thus, it appears that in most studies of humans who do not smoke, nicotine has antinociceptive effects in a clinical setting, but in smokers, receptor desensitization and/or withdrawal effects may limit any analgesic effects of perioperative nicotine administration. Larger confirmatory studies in both smokers and nonsmokers are needed to determine whether nicotine administration has the potential to be a useful adjunct analgesic. Studies are also needed to determine whether the side effects of perioperative nicotine administration can be tolerated. Available studies indicate that intraoperative nicotine does not produce marked hemodynamic changes,123 but it may be associated with increased postoperative nausea,124 a well known effect in nicotine-naïve subjects.
Chronic Pain in Cigarette Smokers
Smoking as a Risk Factor for Chronic Painful Conditions
Several epidemiologic studies show an association between smoking and chronic painful conditions. Leboeuf-Yde et al.  performed a systematic literature review on the association between smoking and low back pain based on 47 studies published between 1974 and 1996.127 Many, but not all, studies find a positive association between smoking and low back pain, with the results from studies with larger samples being more likely to reach statistical significance. Goldberg et al.  reviewed publications from 1976 through mid-1997 on the association between smoking and nonspecific back pain and also found that smoking is associated with nonspecific back pain in some, but not all, of the studies.128 Both of these reviews indicated that the lack of consistency among studies regarding dose response, temporality, and reversibility of nicotine-induced analgesia is an important factor to be considered when making conclusions regarding causality. Moreover, potential confounding effects could not be ruled out based on available evidence because many of the studies were of poor methodological quality. Subsequent studies, published after these reviews, based on epidemiologic data collected from both general and occupational health populations across different geographic regions continue to demonstrate the positive association between smoking status and back pain as well as other painful conditions.21–32 However, there are also several more recent studies that failed to find any association between smoking and chronic pain.129–132 Consideration of the potential relationship between smoking status and painful conditions is further complicated by the fact that smoking can produce changes in central nervous function that persist long after subjects stop smoking.133 Thus, there may be a difference in the susceptibility to chronic pain between never and former smokers, which is often not taken into account in clinical studies. Indeed, some studies suggest that an association of smoking history and chronic pain conditions also exists among former smokers.31,33,134 
In addition to these epidemiologic studies, several additional recent prospective cohort studies provide further evidence for a relationship between smoking and chronic painful conditions. A prospective cohort study of adolescents in Finland demonstrated that daily smoking of more than 9 cigarettes at age 16 predicted pain symptoms (adjusted odds ratio [OR] 2.80; 95% CI 1.11–7.09, adjusted for other factors associated with pain) and was associated with persistent low back pain at age 18 among girls, with a clear dose-response relationship (adjusted OR 2.57; 95% CI 1.03–6.46).27 Another longitudinal study in Finland followed a cohort of adolescents for an average of 11 yr and found that daily smoking was one of the strongest risk factors for low back pain hospitalization (adjusted hazard ratio 1.4; 95% CI 1.1–1.7).26 The associations persisted into adulthood. In the same cohort, daily smoking was a risk factor for lumbar discectomy among males (adjusted hazard ratio 1.5; 95% CI 1.1–2.2).135 In a British birth cohort, incident low back pain at age 32 to 33 yr was predicted by moderate or heavy smoking in early adulthood (adjusted OR 1.63, 95% CI 1.23–2.17).32 In a study in young adults in Norway, smoking in 1990 was associated with moderate or severe pain in 1994 (adjusted OR 2.28; 95% CI 1.32–3.94).22 In a longitudinal study following 9,600 twins for 8 yr, smoking at baseline showed a dose-response relationship with low back pain at follow-up (adjusted OR up to 4.0 for those smoking more than 20 cigarettes a day).24 In a Finnish occupational cohort, smoking of long duration (more than 15 yr), increased the risk of incidental sciatic pain (adjusted OR 2.3; 95% CI 1.3, 3.9).28 In a cohort of metal industry employees followed from 1973 to 2000, the adjusted hazard ratio of heavy smokers for hospitalization because of intervertebral disc disorders was 3.4 (95% CI 1.3–9.0) as compared with never-smokers.25 
In addition to the studies showing an increased frequency of chronic painful conditions in cigarette smokers, others suggest that among those with chronic pain, smokers complain of greater pain intensity and an increased number of painful sites.33,34 In patients presenting to pain rehabilitation, fibromyalgia treatment, and face pain clinics, those who smoke cigarettes report more pain and greater functional impairment, including scores measuring life interference and depression.35–37,136 Smokers who have painful conditions are also more likely to have poorer outcomes. In a prospective cohort study of patients with arm pain, smoking status predicted the persistence of pain (OR 3.3, 95% CI 1.6–6.6).137 In a 7-yr prospective cohort study of 34,754 employed men and women, current smoking was among the strongest predictors for future back pain disability (OR 1.4; 95% CI 1.2–1.7).138 In a retrospective cohort of 15,268 active-duty personnel hospitalized for a common musculoskeletal condition between the years 1989–1996, heavy smoking (more than 1 pack/day) was associated with more disability due to knee conditions among males (hazard ratio 1.67; 95% CI 1.26–2.22).139 In a study of Norwegian adults who had reported musculoskeletal pain, smoking was associated with more intense persistent pain (adjusted OR 1.58; 95% CI 1.24–2.00).140 Other studies find that smokers with chronic low back pain experience greater long-term disability than nonsmokers.141–144 
Potential Mechanisms of Chronic Pain in Smokers
Many factors may influence the relationship between smoking and chronic pain, as depicted in figure 2and discussed in the following section. Several of these factors may interact to determine the ultimate impact of smoking on pain.
Fig. 2.  Potential mechanisms of chronic pain in smokers. CO = carbon monoxide; nAChR = nicotine acetylcholine receptor.
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Fig. 2.  Potential mechanisms of chronic pain in smokers. CO = carbon monoxide; nAChR = nicotine acetylcholine receptor.
Altered Processing of Pain.
As described above in the section on pharmacology of nAChRs, exposure to cigarette smoke and nicotine produces analgesia in animal models, but receptor desensitization and tolerance develop quickly after continuous exposure and may persist for a considerable time.57,58,61,64,75,145–147 In addition, withdrawal symptoms develop when nicotine intake is acutely eliminated or reduced and plasma nicotine levels fall below the relatively narrow range that smokers attempt to maintain during wakefulness. Withdrawal symptoms include both somatic complaints (e.g.  , gastrointestinal symptoms and increased appetite) and affective symptoms (e.g.  , craving for cigarettes, depressed mood, anxiety, dysphoria, and irritability).
Chronic exposure to cigarette smoke may change pain perception in smokers compared with nonsmokers (table 2). Compared with nonsmokers, smokers deprived of nicotine tend to have a shorter pain latency to heat pain and reduced tolerance to electrical pain stimulation.148,149 However, the effects of smoking status may depend on both sex and the specific pain stimulus. For example, nicotine-deprived male smokers had higher threshold and tolerance to electrical pain stimulation compared with nonsmokers.10 In a study involving both sexes where smokers were allowed to maintain their smoking behavior to minimize the influence of nicotine deprivation and withdrawal, female smokers had greater threshold and tolerance to tourniquet-induced ischemic pain, whereas male smokers had increased threshold and tolerance to cold pressor pain.118 In contrast, there were no significant differences between nonsmokers and smokers in their threshold or tolerance to heat pain, regardless of sex. The clinical significance of these stimuli-dependent differences in pain perception is not clear; indeed, when smoking status does affect perceptions in these experimental studies, it tends to blunt the perception of pain, which seems inconsistent with the increased frequency of painful disorders in smokers.
Table 2.  Comparison of Baseline Responses to Experimental Pain Stimuli between Smokers and Nonsmokers
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Table 2.  Comparison of Baseline Responses to Experimental Pain Stimuli between Smokers and Nonsmokers
The interaction between pain and smoking might also reflect pain-induced reinforcement of smoking behaviors. A recent randomized experimental study reported that pain caused by cold pressor stimulation resulted in a shorter latency to smoke and that this process was fully mediated by self-reported pain-induced urge to smoke.150 The effects of smoking on pain could reinforce smoking behavior by increasing the threshold for pain perception or serving as a coping strategy for the pain. In addition, nicotine withdrawal may enhance perception of pain. In animal models, nicotine withdrawal is associated with increased sensitivity to pain stimuli.57,76,82,83 Thus, smokers may perceive a given stimulus as more painful (at least while deprived of cigarettes) and may smoke to relieve increased pain perceptions caused by incipient nicotine withdrawal when nicotine blood levels fall (e.g.  , during sleep). Indeed, smoking a cigarette acutely increases the threshold and/or tolerance to thermal pain stimuli in smokers deprived of nicotine.9,11,13,110–112 However, smoking does not consistently affect acute responses to electrical pain stimuli in deprived smokers.12,113,114,116,148,149,151 It is not clear which (if any) of these stimuli are most clinically relevant to chronic pain states.
Smoking also causes changes in the neuroendocrine system that could modulate pain perception. In general, the stress response (sympathetic and hypothalamic-pituitary-adrenal activation) causes a decrease in pain perception. Although smoking a cigarette can acutely increase these measures, chronic activation by smoking actually can down-regulate these systems, with impaired baroreceptor function and decreases in β-endorphin levels.118,152–155 The normal relationship between stress-induced increases in measures of hypothalamic-pituitary-adrenal activation and analgesia is absent in smokers, providing evidence for smoking-induced dysregulation in endogenous systems that regulate pain. Sex-specific neuroendocrine mechanisms may also contribute to the sex differences in the effect of smoking on pain; for example, estradiol concentrations are chronically reduced in women smokers whereas norepinephrine concentrations are increased only among male smokers.118 
Structural Damage to Other Systems.
In addition to the changes in pain processing, smoking can induce structural changes in other systems that will predispose patients to painful conditions. Smoking is a risk factor for osteoporosis, lumbar disc diseases, and impaired bone healing.156–158 One of the possible underlying mechanisms is that cigarette smoking impairs oxygen delivery to tissues by increasing sympathetic outflow and carboxyhemoglobin levels.159–162 Thus, smoking may accelerate degenerative processes which make the body more vulnerable to injury. Smoking also can interfere with wound healing, which could contribute to prolonged pain after trauma, surgery, or other injuries.163 
Association with Depression.
Symptoms of depression are more common in smokers as compared with nonsmokers.164–167 It is possible that smoking may increase susceptibility to the development of depression. Many smokers report that smoking elevates their mood, so smoking may represent a “self-medication” of depression by cigarettes. Indeed, the frequency of smoking is very high in patients with a variety of psychiatric disorders,168–170 and this explanation is frequently invoked to explain this association. It may also be possible that susceptibility to nicotine dependence and depression share a common etiology. In addition, depression is linked to painful symptoms. Depression and pain share biologic pathways, and both are influenced by common biologic and social factors.171–174 Symptoms of depression are relatively common in patients with chronic pain, and antidepressants are a frequent component of pain therapy. Thus, there may be a complex relationship among smoking, chronic pain, and depression, but few data exist that are useful in exploring this potential relationship.
Psychosocial Factors.
As the prevalence of smoking has declined, the demographic characteristics of those who smoke have changed. Recent social network analyses show that smokers form isolated “clusters” that are becoming increasingly marginalized from others in society.175,176 Smoking is also associated with poorer socioeconomic status, lower educational attainments, higher rates of divorce, and higher rates of unemployment.1 These demographic characteristics are also observed among smokers who seek care for their painful symptoms.35–37,136,177 Lower socioeconomic status and other psychosocial stressors are also related to a higher prevalence of chronic pain and poorer outcomes.178–181 All of these factors may impair the ability of individuals to cope with their pain symptoms and thus contribute to chronic painful states. However, such psychosocial factors do not entirely explain the increased severity of painful conditions in smokers, as recent studies show that the symptoms of smokers presenting to a pain clinic in a tertiary care center were more severe than those of nonsmokers, even after controlling for demographic factors.36,37,136 
Opioid Use.
A recent population-based study shows that current and former heavy smokers are more likely to use prescription analgesic drugs than never-smokers.182 Among patients who were admitted to a pain rehabilitation program, smokers had a greater proportion of opioid use as well as a higher mean morphine equivalent dose compared to former smokers and never-smokers.183 Further analysis suggested that male smokers consumed a greater quantity of opioids compared with female smokers.184 Interaction between nAChRs and opioid receptor pathways may contribute to the use of opioid analgesics by smokers.
Opioid pathways may modulate both the analgesic effects of nicotine (as described in the section on animal studies) and the reinforcing properties of smoking that contribute to addiction. Indeed, cross-tolerance between nicotine and morphine is present in mice.185 In humans, methadone use increases cigarette smoking,186,187 whereas opioid antagonist naltrexone attenuates smoking behavior.188,189 Mesolimbic dopaminergic pathways may be involved in this process because activation of both nAChRs and opioid receptors stimulates the release of dopamine in the nucleus accumbens in a synergistic fashion.82,190,191 The nucleus accumbens mediates the rewarding effects of nicotine192,193 and modulates pain perception.194,195 Cigarette smoking is also associated with the abuse of alcohol and of illicit drugs, including heroin and cocaine, and there is a very high prevalence of smoking among those who abuse illicit opioids (more than 90%).196 Thus, common behavioral or biologic factors may predispose individuals to nicotine dependence as well as dependence on other drugs, both licit and illicit. Indeed, substance use disorders may result from impaired decision-making ability in opioid-dependent smokers.197 
Exposure to cigarette smoke may also alter the pharmacokinetics of opioids. A study in chronic pain patients showed that smokers reported higher pain scores and required more hydrocodone, but had lower serum hydrocodone levels, compared with nonsmokers.198 Polycyclic aromatic hydrocarbons, a group of carcinogenic substances in cigarette smoke, substantially influence the activity of liver cytochrome P450 enzymes, primarily CYP1A2 and possibly CYP2E1.199 In addition, UGT2B7, a subtype of uridine-diphosphate glucuronosyl transferase, is induced by polycyclic aromatic hydrocarbons.200–202 Because morphine is primarily metabolized by these transferases, their induction may enhance morphine metabolism.203,204 Furthermore, UDP-glucoronosyl transferase function may be modulated by CYP3A4.205 However, how smoking status affects the metabolism of morphine and other opioid analgesics is still unclear.
Other Effects of Cigarette Smoking.
Although most attention has been focused on the effects of nicotine on pain, any of the approximately 3,000 other constituents of cigarette smoke may also be involved in the development of painful conditions. For example, chronic exposure to carbon monoxide increases the level of heme oxygenase.206,207 The heme oxygenase-carbon monoxide system influences a variety of cellular processes, including inflammation, oxidative stress, and apoptosis,208 and heme oxygenase may participate in the development of neuropathic pain.209 The possible involvement of the heme oxygenase-carbon monoxide system in the susceptibility of smokers to chronic pain needs further study.
In summary, current evidence supports the finding that smoking is a risk factor for chronic painful conditions, but several aspects of this relationship require further study. The complex relationship between the multiple factors associated with smoking (fig. 2) needs to be explored to elucidate the mechanisms responsible for this interaction. For example, more data are needed to determine whether smoking per se  contributes to the development of pain, or whether it is a marker for other conditions such as depression or psychosocial factors that themselves are causal. To this end, studies need to carefully assess smoking history and to measure and control for the many other factors that may be associated with pain, including demographic factors, coexisting medical conditions, and medication use. Experimental human studies examining the effects of smoking and/or nicotine on pain need to carefully consider smoking history, including the extent of nicotine dependence as well as the withdrawal state of the subjects. The range of experimental pain models studied should be expanded, and their relevance to clinical painful conditions considered. The high prevalence of smoking and the large population affected by smoking related conditions or secondhand smoke make these studies urgently needed.
Clinical Implications
Management of Postoperative Pain in Cigarette Smokers
There are relatively few clinical studies of how smoking status affects acutely painful conditions in general and postoperative pain in particular. Several studies examined postoperative opioid consumption. After third molar extraction, those smoking more than 10 cigarettes a day used significantly more acetaminophen/codeine tablets compared with nonsmokers and light smokers, although the difference was modest (mean of 0.6 tablets).210 A retrospective review of patients undergoing coronary artery bypass grafting demonstrated that smokers had a 33% greater opioid requirement in the first 48 h after surgery.211 However, factors other than smoking status that are known to influence postoperative opioid use, such as age, sex, opioid tolerance, and surgical characteristics, were not controlled. In addition, female former and current smokers used more opioid analgesics than female never-smokers after gynecologic surgery.212 All of these studies were observational, none attempted to analyze possible covariates that might influence opioid consumption, and none reported the level of analgesia achieved. In a general surgical population, smokers reported higher pain scores both before and after surgery but did not experience greater increases in pain postoperatively compared with nonsmokers,213 although pain was only a secondary endpoint in this study and the study included a heterogeneous surgical population. Thus, based on the limited available evidence, increased postoperative analgesic requirements might be anticipated in cigarette smokers, although whether this effect (if present) is of sufficient magnitude to warrant a change in clinical approach (e.g.  , a more aggressive use of regional analgesia) is not clear. Clearly more data are needed from carefully conducted prospective clinical studies.
As discussed above in the section on human studies–postoperative pain, some (but not all) studies find that systemic nicotine can contribute to postoperative analgesia in nonsmokers; whether nicotine replacement therapy could contribute to postoperative analgesia in smokers, both by preventing nicotine withdrawal and through the systemic effects of nicotine on pain perception, is unclear. However, in several placebo-controlled studies, nicotine patches did not improve postoperative analgesia in smokers,125,126,214 nor did they affect nicotine withdrawal symptoms, which were minimal even in those smokers receiving placebo.214 Thus, there is no evidence to suggest that routine perioperative nicotine replacement therapy in smokers will improve postoperative analgesia, although it may be efficacious in helping these patients maintain postoperative abstinence after hospital discharge,205 which has several other benefits.
Outcomes of Chronic Pain Therapy in Smokers
The complex relationship between smoking, pain, and other comorbid conditions such as depression and substance use disorders may pose additional challenges to the treatment of smokers with painful symptoms. As discussed in the section on chronic pain, smokers presenting to pain treatment programs report more pain and greater functional impairment compared with nonsmokers.35–37,136 Fishbain et al.  found that current smokers were less likely to be employed compared with nonsmokers after multidisciplinary treatment for low back pain, implying more persistent disability.215 Weingarten et al.  observed that 50% of smokers presenting to an outpatient tertiary pain clinic were unemployed or disabled, compared with 18% of nonsmokers.36 However, Hooten et al.  reported that in an observational study of outcomes from a 3-week multidisciplinary pain rehabilitation program, despite the greater pain and functional impairment reported by smokers at program entry, their treatment responses were either not different or actually better than for nonsmokers.35 Importantly, the 3-week treatment program also incorporated an aggressive attempt to taper opioid use in those patients who were opioid-dependent, and nearly all participants discontinued opioid use. Success in opioid tapering in this program did not depend on smoking status, regardless of sex.35,184 Thus, it appears that smoking status does not prevent successful cognitive behavioral therapy and rehabilitation for pain treatment.
Smoking Cessation Interventions in Chronic Pain Patients
Smoking is the leading preventable cause of premature death in the United States.216 A primary recommendation of the Clinical Practice Guideline for Treating Tobacco Use and Dependence is that whenever patients contact the health care system, a systematic effort should be made to identify tobacco users, strongly urge them to quit, and provide aid to do so.217 Consideration of the potential role of clinician interventions to address smoking as a part of pain therapy raises several interesting issues.218,219 Certainly, patients with chronic pain, like all other patients, would enjoy the dramatic benefits of smoking cessation on long-term health. However, there are also concerns. Given the complex relationship among pain, smoking, and comorbid conditions such as depression and substance use disorders, it is not clear how tobacco abstinence would affect pain symptoms, either in the short or longer term. In the short term, to the extent that systemic nicotine provides acute analgesia, abstinence might acutely worsen painful symptoms and remove a means that many smokers perceive as useful in controlling stress and anxiety. Nicotine withdrawal symptoms accompanying acute abstinence might also complicate concurrent efforts to treat pain. In the long term, recovery from the effects of long-term exposure to nicotine may improve chronic painful states, although this remains to be determined. Adoption of coping strategies other than smoking may also improve adaptive responses to persistent pain and improve functional status.
Although data are very limited, it appears that motivation and intent to quit smoking is similar in smokers with and without chronic pain.220 However, observational studies suggest that very few smokers entering chronic pain treatment successfully quit, even when offered efficacious tobacco intervention services.35,215 Thus, there is an urgent need for more research about how tobacco abstinence affects chronic pain and the development of effective methods to help smokers with chronic pain quit. There may be an instructive parallel with psychiatric disease. Psychiatric hospitals were among the last healthcare facilities to ban smoking because of the high prevalence of smoking among these patients and the assumption that abstinence would worsen mental health outcomes.221,222 However, experience has shown this not to be the case, and now considerable efforts are under way specifically targeting tobacco interventions to these patients.223–227 A similar approach may be warranted for the chronic pain patient. However, such approaches will require a sufficient evidence base regarding the acute and chronic effects of abstinence on painful conditions, and the development of practical, efficacious interventions that can be readily applied in the clinical setting.
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Fig. 1.  Schematic representation of the potential sites of analgesic action of nicotine. In the central nervous system, there is widespread distribution of homomeric α7 and heteromeric α4β2* nicotinic acethylcholine receptors (nAChR), including regions associated with pain transmission such as the dorsal horn, locus ceruleus, and thalamus. The α9α10 nAChR is present in dorsal root ganglia. Many anesthetics also modulate or inhibit nAChR function. Activation of supraspinal and spinal nAChR results in opioid and norepinephrine (NEpi) release, which can reduce descending facilitatory pain pathways (green  ) and enhance descending inhibitory pain pathways (red  ), resulting in reduced transmission of nociceptive input (blue  ).
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Fig. 1.  Schematic representation of the potential sites of analgesic action of nicotine. In the central nervous system, there is widespread distribution of homomeric α7 and heteromeric α4β2* nicotinic acethylcholine receptors (nAChR), including regions associated with pain transmission such as the dorsal horn, locus ceruleus, and thalamus. The α9α10 nAChR is present in dorsal root ganglia. Many anesthetics also modulate or inhibit nAChR function. Activation of supraspinal and spinal nAChR results in opioid and norepinephrine (NEpi) release, which can reduce descending facilitatory pain pathways (green  ) and enhance descending inhibitory pain pathways (red  ), resulting in reduced transmission of nociceptive input (blue  ).
Fig. 2.  Potential mechanisms of chronic pain in smokers. CO = carbon monoxide; nAChR = nicotine acetylcholine receptor.
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Fig. 2.  Potential mechanisms of chronic pain in smokers. CO = carbon monoxide; nAChR = nicotine acetylcholine receptor.
Table 1.  Effects of Smoking and Nicotine on Experimental Pain in Humans
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Table 1.  Effects of Smoking and Nicotine on Experimental Pain in Humans
Table 2.  Comparison of Baseline Responses to Experimental Pain Stimuli between Smokers and Nonsmokers
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Table 2.  Comparison of Baseline Responses to Experimental Pain Stimuli between Smokers and Nonsmokers