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9 Articles in Volume 17, Issue #9
Can Physiological Profiles Affect Pain Treatment?
Editorial: Moving Forward from Trump's Opioid Declaration
How Might Pain Practitioners Best Offer Patients Relief Without Pharmacology?
Letters to the Editor: An opportunity to learn what is on the minds of your colleagues and patients
Lumbar Lordosis and Back Pain
Oxytocin, an Opioid Alternative, Ready for Regular Clinical Use to Manage Chronic Pain
Pain, Sleep & Suicide: The Core Role of Interventional Care
Spiritual Factors Impacting a Patient’s Ability to Cope with Uncertainty (Part 3)
The Inter-Connection between Smoking and Opioid Misuse

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.

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

There is further suggestion that cigarette smoking adversely affects serum hydrocodone levels.16 Smokers had higher pain scores and required more hydrocodone than nonsmokers in a 2007 study.16 In another study, the prevalence of smoking among patients on methadone ranged between 73.5% and 94%.17 Qiu et al indicated that smokers have hyperalgesia perioperatively. The authors attributed this to desensitization and competitive occupancy of nAChR for binding sites.18 Smokers were found to have higher pain scores and higher need for opioids during surgery and postoperatively compared to nonsmokers.18 Indeed, evidence supports that nicotine can act as an introducer and a gateway for the use of other illicit substances, and that smoking is a strong predictor of risk for nonmedical use of opioids.19 Nicotine induces dopamine release facilitated by the opioid system and the nicotinic-acetylcholine system modulates self-administration of many abused drugs.19

Patient Profile

In cancer patients, researchers found that smokers had significantly higher pain intensity and a higher rate of opioid misuse than nonsmokers.20 A retrospective cross-sectional study on chronic non-malignant Danish pain patients found smokers and former smokers tended to use opioids more frequently and at higher doses than nonsmokers.21 Another cross-sectional analysis of veterans showed higher likelihood of receipt of an opioid prescription in smokers than nonsmokers.22

In heroin-addicted Italian patients attending opioid-substitution therapy, the prevalence of smoking was 97.2%; 64.3% of whom were living with smokers.23 McKelvey et al at the University of California San Francisco’s Center for Tobacco Control Research and Education published findings of more than 20 studies on the positive impact of smoking cessation on substance-use disorder (SUD) outcomes.24 The authors concluded that “not offering smoking cessation in SUD was tantamount to increased harm.”24

The Psychological Factor

Joseph Ditre, PhD, a leading psychologist researcher at Syracuse University, conducted an informational interview with Practical Pain Management regarding psychological mechanisms behind smoking and chronic pain. He suggested a “patient’s perception” may be an important motive for smoking among patients with chronic pain. “Patients may be motivated to continue smoking, in part, due to the pain they are experiencing and their desire to reduce it or distract themselves from it…tobacco smoking might be seen as one of the few things they can still enjoy,” said Dr. Ditre.25

In a previous article, the authors proposed three potential explanations of the relationship between aberrant drug-taking behavior and smoking. These included: pseudoaddiction, substance abuse disorders, and chemical coping/negative affect reduction.26 In the latter, smokers tried to elevate their negative mood/effect by smoking as a means to adjust their mood regulation.26

Another expert in the field attributed depression, in part, to explain pain severity differences among smokers versus nonsmokers. W. Michael Hooten, MD, professor of anesthesiology at the Mayo Clinic, suggested that smokers “will be at risk for reporting greater levels of pain, which could be due, in part, to elevated levels of depression.” He recommended that patients with chronic pain who smoke should be carefully assessed for depression, noting that “prompt and intensive treatment of depression could, in turn, lead to improvements in pain-related symptoms among smokers with chronic pain.”27

Clinical Vignette: Patient Education and Readiness

A 64-year-old man was referred to the authors’ clinic by his primary care provider (PCP) for treatment of low back pain. His medical history included significant coronary artery disease, hypertension, hyperlipidemia, type 2 diabetes, chronic obstructive pulmonary disease, and ongoing smoking since age 16, with an average of 25 cigarettes a day. His past surgical history included coronary artery bypass grafting (4) and laminectomies at L4-5 and L5-S1, followed by posterior fusion at L4 to S1 one year later. He worked as a landscaper and is divorced. He continued to complain of leg pain despite the fusion. His medications included:

  • Diazepam (5 mg bid for “spasms”)
  • Tramadol (50 mg II qid prn)
  • Hydrocodone/APAP (10/325 mg II qid prn pain)
  • Metoprolol (25 mg bid)
  • Glipizide
  • Lipitor
  • Lisinopril
  • Plavix
  • Aspirin.

He tried lumbar epidural injections a few years prior with limited relief. Physical therapy trial worsened his symptoms due to: his sedentary lifestyle; deconditioning related to chronic smoking; history of coronary artery disease, as well as back fusion and laminectomies; and a lack of motivation related to chronic use of diazepam and hydrocodone. The patient admitted to taking more hydrocodone and tramadol than prescribed. His PCP told him she was “unable to prescribe pain medications anymore.”

Our initial approach with this patient was directed toward establishing a good relationship based on mutual trust, which required time. His previous treatment plan had led to repeated early refills on pain medications and continued leg pain. Rather than advising on lifestyle from the start, our focus on bonding helped him understand that we had his best interests in mind. It is difficult to tell a patient to “stop smoking” after only a few minutes of face-to-face evaluation.

Patient education was interdisciplinary and adjusted according to the level of readiness and comprehension. Evaluation with electromyography and nerve conduction velocity, lumbar MRI, and an evaluation to rule out peripheral arterial/vascular disease will be recommended in the second phase of treatment, depending on urgency of the diagnosis and pain levels. The authors recommended doing this work-up as part of the second or third appointment.

Research by Steven Passik, MD, director of Clinical Addiction Research and education at Millennium Laboratories in San Diego, suggests that pseudoaddiction in this patient be evaluated.26 The patient was working as a landscaper but only part-time; he was not sedentary and did his best to work despite the pain and lumbar fusion.

Per research by Dr. Hooten, the patient should be evaluated for underlying depression as well, and if diagnosed, treated accordingly.27 After patient education, pain medication may be addressed, as well as the possibility of using benzodiazepine. Further, an adequate management plan that includes nicotine replacement therapy may be put into place.


Healthcare providers must not give up on talking to patients about smoking cessation. Ongoing patient education should clarify that smoking not only interferes with pain perception, pain scores, and pain medication use, but also may affect the healing process and general wellbeing. It behooves practitioners to continue educating patients about how smoking may precipitate opioid misuse, thereby offering the best chance to motivated patients, especially in these times of opioid limitations.

Last updated on: January 3, 2019
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