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The Inter-Connection between Smoking and Opioid Misuse

Patients with chronic conditions using cigarettes to alleviate pain symptoms may actually be increasing their pain and upping their risk of opioid misuse.
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While the percentage of Americans who smoke has declined significantly over the past few decades,1,2 physicians treating chronic pain must be aware of patients’ smoking habits as there are direct correlations with pain perception, scores, and medication use. Patients who smoke also have a higher likelihood of opioid misuse. This article reviews the latest scientific evidence linking nicotine use to opioid use, and highlights the need for practitioners to speak to their patients about the importance of smoking cessation.

Nicotine as an Instigator

Nicotine is a major component of chemicals contained in cigarettes. The quick absorption of nicotine in the blood stimulates the adrenals to release epinephrine, which then incites the central nervous system (CNS) causing increased heart rate, respiratory rate, and blood pressure.3 Nicotine also increases the levels of dopamine, which controls pleasure and reward, just as in heroin and cocaine.3 The chronic exposure to nicotine, may lead to addiction to nicotine, in particular, and act as a gateway to possible addiction in general.3

While nicotine directly affects epinephrine and dopamine levels in the brain, there is data to suggest its role in endogenous opioids circuitry as well. In 2014, Hiroto Kuwabara, MD, PhD, an assistant professor in the School of Medicine at Johns Hopkins University, and his research team used positron emission tomography brain scans to assess the binding potential of endogenous opioids in the brains of smokers and nonsmokers.4

In subjects smoking placebo cigarettes, there was a positive correlation of binding of endogenous opioids to mu opioid receptors (MOR) in the superior temporal cortex leading to dependence on nicotine. In the frontal cortex, increased binding of endogenous opioids to MOR was associated with self-reports of liking and wanting cigarettes, suggesting a role of the brain’s opioid system in cigarette addiction.4

The Antinociceptive Effect

In a prior review article, the authors listed the physiologic effects of nicotine. 5 It is an agonist of nicotinic acetylcholine receptors (nAChRs), which are found throughout the peripheral and the central nervous system (CNS).5 These areas include the dorsal horn, locus ceruleus, and thalamus.5,6 Nicotine acts on the α3β4 ganglion type in the autonomic ganglia and adrenal medulla, and the α4β2 nicotinic receptors in the CNS.6, 7 The increased binding of nAChRs produces central antinociceptive effects that activate the pain-inhibitory pathways descending down the spinal cord, resulting in discharge of epinephrine from the adrenal medulla and catecholamines from sympathetic nerve endings.8

In clinical encounters with chronic pain patients, many claimed an analgesic effect from smoking. This observation was also made in a 1979 study.9 Nicotine exerted an analgesic effect on thermal stimuli as reflected by the tail-flick test that can be easily blocked by nicotinic blockers. Researchers suggested that nicotine reduced painful stimuli by a central release action on acetylcholine. In 2008, another study team’s findings suggested that nicotine and metanicotine were effective in heat and pressure testing in mice and reconfirmed a α4β2 nicotine antinociceptive effect.10


Drug addiction involves more than neurobiological hypotheses. It is a chronic impulsive and compulsive state, characterized by abnormal drug taking that involves compulsion to seek/take the drug, loss of control, and emergence of negative emotions when the drug is not available.11 This pathological disorder encompasses stages of binge/intoxication, preoccupation/anticipation (craving), and withdrawal symptoms. Different areas of the brain are involved at each stage and the individual’s transition to addiction involves neuroplasticity in the corresponding areas.11

In 2011, a report from the University of Pennsylvania’s Center for Interdisciplinary Research on Nicotine Addiction postulated that the MOR is particularly involved in mediating the nicotine rewarding effect. A single nucleotide polymorphism (SNP) in the human MOR gene (OPRM1 A118G) was shown to alter receptor protein level in smoking behavior.12 It has been further documented that nAChR in the brain influences reward, addiction, and withdrawal symptoms.13 Nicotine enhances the firing rate and the phasic bursts by midbrain dopamine neurons.13 When chronically exposed to nicotine, neuro-adaption and upregulation are likely to ensue, and when nicotine is withdrawn, a withdrawal syndrome may take place.13

Smoking & Opioid Therapy

Compared to nonsmokers, smokers treated with chronic opioid therapy for nonmalignant pain use higher doses of opioids, putting them at increased risk of misuse and dependence on opioids.14 Recent research indicates that, despite having an opioid misuse disorder and being on higher opioid doses, current and former smokers were resistant to decrease chronic opioid therapy; they perceived they had lesser problems with opioid use.14 A separate study conducted in Germany found that current and former heavy smokers were more likely to use analgesic drugs than nonsmokers.15

Last updated on: November 9, 2017
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