Journal of Anesthesia
https://doi.org/10.1007/s00540-022-03097-w

GUIDELINE

Consensus statement on smoking cessation in patients with pain
Hiroki Iida1,2,11 · Shigeki Yamaguchi1,3 · Toru Goyagi1,4 · Yoko Sugiyama1,5,11 · Chie Taniguchi1,6 ·Takako Matsubara1,7 · Naoto Yamada1,8 · Hiroshi Yonekura1,9 · Mami Iida1,10Received: 5 June 2022 / Accepted: 13 August 2022
© The Author(s) 2022

Abstract
Smoking is closely associated with the development of various cancers and tobacco-related illnesses such as cardiovascularand respiratory disorders. However, data are scarce on the relationship between smoking and both acute and chronic pain. In
addition to nicotine, tobacco smoke contains more than 4000 different compounds. Although nicotine is not the sole causeof smoking-induced diseases, it plays a critical role in pain-related pathophysiology. Despite the acute analgesic effectsof nicotine, long-term exposure leads to tolerance and increased pain sensitivity due to nicotinic acetylcholine receptor
desensitization and neuronal plastic changes. The purpose of smoking cessation interventions in smoking patients withpain is primarily not only to reduce their pain and associated limitations in activities of daily living, but also to improve theoutcomes of underlying pain-causing conditions and reduce the risks of tobacco-related disorders. This statement aims tosummarize the available evidence on the impact of smoking on pain and to inform medical professionals of the significanceof smoking cessation in patients with pain.
Keywords Acute pain · Chronic pain · Smoking cessation · Withdrawal · Nicotine

Basic principles and overview
Purpose of this document
Smoking is closely associated with the development of various diseases, including the following: lung, laryngeal, andother cancers; myocardial infarction, stroke, and other cardiovascular diseases; and respiratory disorders such as chronic
obstructive pulmonary disease and asthma. However, data

6

College of Nursing, Aichi Medical University, Nagakute,
Japan

7

Department of Physical Therapy, Faculty of Rehabilitation,
Kobe Gakuin University, Kobe , Japan

8

Department of Anesthesiology and Pain Medicine, Gifu
University Graduate School of Medicine, Gifu, Japan

Department of Anesthesiology, Iwate Medical University
Hospital, Iwate, Japan

9

Department of Anesthesiology, Dokkyo Medical University
School of Medicine, Tochigi, Japan

Department of Anesthesiology and Pain Medicine, Fujita
Health University Bantane Hospital, Nagoya, Japan10

Department of Anesthesiology, Akita University Hospital,
Akita, Japan

Department of Internal Medicine, Gifu Prefectural General
Medical Center, Gifu, Japan

11

Anesthesiology and Pain Relief Center, Central Japan
International Medical Center, 1‑1 Kenkonomachi,
Minokamo, Gifu 505‑8510, Japan* Hiroki Iida
h-iidamd@xqd.biglobe.ne.jp
1

2

3

4

5

are scarce on the relationship between smoking and acuteand chronic pain. Smoking patients are often refractory topain control. Until recently, there was a lack of consensus
regarding smoking treatment options that optimize pain
relief.
This statement aims to summarize available evidence on
the impact of smoking on pain, inform clinicians and other
health care professionals of the significance of smoking

Working Group on the Role of Smoking Cessation in Pain
Relief, The Japan Society of Pain Clinicians (JSPC), Tokyo,
Japan

Department of Woman Doctor Active Support
in Perioperative Medicine, Gifu University Graduate Schoolof Medicine, Gifu, Japan

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Journal of Anesthesia

cessation in patients with pain, and describe the role ofsmoking cessation in multidisciplinary pain management.

Target audience
This document is intended for healthcare professionals who
manage pain in smoking patients and those who provide
smoking cessation therapies for patients with pain. Smoking
patients who visit general physicians, surgeons, and otherspecialists often complain of pain. This document will help
physicians, nurses, pharmacists, physical therapists, andother healthcare workers deal with smoking patients in their
daily work.

Levels of evidence and gradesof recommendations
Search strategy
In July 2020, we conducted a systematic search of the literature on smoking cessation and pain relief using MEDLINE(PubMed). Search terms included “smoking,” “tobacco,”“smoking prevention,” “smoking cessation,” “smoking cessation aid,” “nicotine,” “tobacco use disorder,” “analgesia,”“analgesic,” and “pain.” The literature search covered theperiod from January 2000 to June 2020. The specific search
formulas are shown in the Appendix. In addition, references
cited in the articles identified by the MEDLINE literaturesearch were examined, where appropriate, when preparing
answers to each clinical question. Our search was limited tostudies published in English or Japanese. Published clinicalguidelines and systematic reviews were assessed for quality,
recency, and relevance before adopting them.

Quality of evidence and strengthsof recommendations
The quality of evidence and strength of a recommendation
were assessed based on the “Minds Manual for Guideline
Development 2017” [1] and “GRADE System for Clinical
Practice Guideline, Third Edition” [2].
The overall quality of evidence on outcomes was categorized as follows:
A (high): We are very confident that the true effect lies
close to that of the estimate of the effect.
B (moderate): We are moderately confident in the effectestimate.
C (low): Our confidence in the effect estimate is limited.
D (very low): We have very little confidence in the effectestimate.

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The strength of a recommendation was assessed based onfour factors: overall quality of evidence, balance between
desirable and undesirable effects, values and preferences,and use of costs and resources. The strength of a recommendation was categorized and presented as follows:
1: Strong
2: WeakBecause of the nature of research, most studies on smoking cessation related to pain relief were cohort based, andthere was a limited number of randomized controlled studies
and systematic reviews. When the findings of our systematic
literature search could not be formulated, we made no recommendation and did not indicate their strength or evidence
quality.
Each recommendation is accompanied by its strength (1or 2) and evidence quality (A, B, C, or D).
The study designs of individual references were classified
into the categories below. As supplementary information,
the category of each study is shown in brackets following
its citation in the Reference Section.
Ia: Systematic review/meta-analysis
Ib: Randomized controlled trial
IIa: Non-randomized controlled trial or large-scalecohort study (n ≥ 500)
IIb: Analytic epidemiologic study: small-scale cohort,case-control, or cross-sectional
III: Descriptive study: case report or case series report
IV: Laboratory experiments and others

Criteria for recommendations and consensus
building
A draft version of this document was distributed to each
Working Group member for review and comments. Working
Group members were asked to confirm the text. After feedback comments were received, a consensus building meeting
was held with all members in attendance. Consensus on each
proposed recommendation was reached when at least 80% ofmembers agreed. Discussions continued until the consensus
criteria were met.

Public comments from related academic societies
The Working Group solicited public comments on the draft
version of this document from members of the Japan Societyof Pain Clinicians (JSPC) and related academic societies.
The Working Group discussed the comments received anddecided whether to accept or reject them.

Journal of Anesthesia

Basic physiology of pain and tobaccosmoking

effects of cigarette smoking

Objectives of smoking cessation in patientswith pain
The primary objective of smoking cessation interventions
in smoking patients is to alleviate their pain and associated limitations in activities of daily living (ADLs).
Other objectives include improving the outcomes of theunderlying pain-causing conditions and reducing therisks of tobacco-related disorders. Thus, smoking cessation interventions contribute to the goal of helping people
lead healthy and fulfilling lives and improving their life
expectancy.

Pain and smoking
Tobacco smoke contains nicotine, carbon monoxide, andmore than 4000 other compounds. Although nicotine is not
the sole cause of smoking-induced diseases, it plays a critical role in pain-related pathophysiology. Its effects on pain
perception are complex. Experimental and human models
show that nicotine has acute analgesic effects that are mediated by the activation of nicotinic acetylcholine receptors(nAChRs) in the central and peripheral nervous systems[3–6]. These receptors control the release of noradrenaline,
endogenous opioids, dopamine, and other neurotransmittersthat activate the descending pain modulatory pathway or
suppress the nociceptive input to the spinal dorsal horn [7,8]. Long-term exposure to nicotine induces tolerance due tonAChR desensitization and neuronal plastic changes, which
together increase the amounts of nicotine to achieve desired
effects. Since nicotine is rapidly eliminated from the brain,
its effects on pain reduction become more complicatedunder chronic exposure conditions, where the impacts of
nicotine withdrawal symptoms and nAChR desensitization
outweigh the analgesic effects of absorbed nicotine, thereby
resulting in elevated pain sensitivity [9] (Fig. 1).
In rat models, pain thresholds change with the durationof nicotine exposure. They increase after 1 to 3 weeks of
exposure, but decrease after ≥ 6 weeks of exposure [12].
In a rat model of neuropathic pain induced by sciatic
nerve ligation, chronic nicotine exposure caused greater
mechanical hyperalgesia than control treatment [16].
Moreover, rats chronically exposed to nicotine exhibiteddecreased pain thresholds and hyperalgesia following nicotine withdrawal [17, 18], suggesting the involvement of
α7-type nAChRs (α7-nAChRs) [19]. Increased pain perception associated with nicotine withdrawal may involve
changes in peripheral and central nervous system reactions

Niconein brain(7䡚10sec)

Cigareecraving
NICOTINE
CYCLE

PAIN
Niconewithdrawal

Niconein brain

Dopamine

Pain relief
Pleasureeffects of cigarette smoking

Physical damage
Osteoporosis
Disc degeneraon
Impaired bone healing
Impaired wound healing

Depression

GABA
Niconewithdrawal

CHRONIC PAIN
means increasemeans decrease

Fig. 1  Acute and Chronic Effects of Cigarette Smoking. Top: Acuteeffects of cigarette smoking. Smoking rapidly increases brain concentrations of nicotine (7–10 s). Nicotine binds to nAChRs in the midbrain (ventral tegmental area), and this binding activates dopamine
release at nerve endings in the nucleus accumbens. This dopamine
release causes feelings of pleasure, euphoria, and pain relief [10].
However, brain nicotine levels rapidly decrease, with an elimination
half-life of approximately 30 min. This rapid decrease lowers the cerebral levels of dopamine and other neurotransmitters, leading to nicotine withdrawal symptoms, greater pain intensities, and stronger craving for smoking [11]. One cycle of smoking, reward, withdrawal, andcraving often leads to another. Bottom: Chronic effects of cigarettesmoking. Long-term smoking may cause osteoporosis, disc degeneration, delayed bone and wound healing, and other physical damage[11], and also decrease GABA secretion, desensitize nAChRs, andenhance depressive tendencies [11–13]. Interactions between thesechanges can aggravate chronic pain. Moreover, nicotine withdrawal
symptoms appear between cigarettes, and exacerbate chronic pain
[14, 15]. The nicotine-induced pain exacerbation may further intensify depressive symptoms and chronic pain, thereby contributing to
the vicious cycle of smoking [12, 14, 15]. GABA gamma-aminobutyric acid, nAChR nicotinic acetylcholine receptor(sensitization), endogenous opioid release, and hypothalamic–pituitary–adrenal (HPA) axis regulation [11].
Tobacco smoking has limited acute short-term analgesic
effects. In special circumstances, nicotine may be administered as an analgesic in nonsmokers. However, analgesic

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Journal of Anesthesia

Effects of smoking on pain (pathology)pressor pain threshold than male nonsmokers [21]. Smokers showed evidence for blunted HPA-axis function during
stress, as well as compromised endogenous pain regulatory
mechanisms. Duan et al. found that whereas smokers had ahigher preoperative pressure pain threshold than nonsmokers, the incidence of inadequate postoperative analgesia wassignificantly greater in smokers [22]. Female smokers had
significantly lower cold pressor pain tolerance than both
female nonsmokers and smoking and nonsmoking men [23].
Nicotine withdrawal enhances pain perception. Smokers
experienced greater pain during the first 12–24 h of smoking
abstinence [14, 15]. The levels of nicotine dependence werepositively associated with greater pain intensity [24, 25].
Smokers abstinent for < 1 month had lower thresholds forelectrically evoked pain than nonsmokers. These findings
indicate that nicotine withdrawal lowers pain thresholds andcauses hyperalgesia in long-term smokers who have beenchronically exposed to and dependent on nicotine. Since it is
not literally possible for smokers to keep smoking throughout the day to prevent withdrawal symptoms, nicotine withdrawal that occurs during abstinence unavoidably elevates
the risk of hyperalgesia.

Does smoking affect pain sensation?

Is smoking associated with pain?

< Summary Statements >< Summary Statements >• Smoking and nicotine administration provide acute anal-• Smokers have a higher prevalence of chronic pain andeffects of tobacco smoking are limited and short-term. Generally, individuals chronically exposed to tobacco smoke arestrongly affected by the interplay between nicotine-induced
temporary analgesic effects and increased pain sensitivity
due to nicotine withdrawal [10, 14]. Complex smoking andpain relationships may develop as a result of interactions
involving the following factors: (i) alteration in pain processing due to chronic nicotine exposure; (ii) interaction
with opioids and other analgesics; (iii) structural damage toskeletal and other systems, resulting for instance in osteoporosis, spinal degenerative disease, delayed bone, and woundhealing; (iv) development or worsening of depression andother psychiatric symptoms, and (v) poor socioeconomic
conditions [11]. As a result of these and other factors, pain
sensitivity increases after long-term nicotine exposure.
In Sect. 4, we discuss various tobacco-related problems
in detail.

Clinical questions

gesic effects.
• Pain threshold and tolerance levels differ between smokers and nonsmokers.
• Nicotine withdrawal increases pain in smokers.
< Commentary >Receptors of nicotine, the key component of tobaccosmoke, are widely distributed in the central and peripheral nervous systems, and are involved in the physiology
of arousal, sleep, anxiety, cognition, and pain. Nicotine
activation of nAChRs gives rise to acute analgesic effects
in animal models and humans [11]. In humans undergoingexperimental pain induction, nicotine or tobacco administration conferred acute analgesic effects of small-to-moderatemagnitude [10]. A meta-analysis of studies on intranasal ortransdermal nicotine for the treatment of postoperative pain
showed a reduction in postoperative pain at 24 h comparedwith placebo, but the effects were relatively small [20].
However, chronic exposure to nicotine, as observed inlong-time smokers, is associated with complex changes inpain threshold and tolerance. Girdler et al. reported thatfemale smokers had a greater ischemic pain threshold thanfemale nonsmokers, and male smokers had a greater cold

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greater pain intensity than nonsmokers.

• Smoking exacerbates nociceptive, neuropathic, and psy-

chosocial pain.

• Acute pain is more likely to become chronic in smokers.
• Smokers tend to experience worsening of pain-related

pathologies (e.g., mood disorders, depression, and sleep
disturbance), ADLs, and social activities.
• Smoking increases the risks of osteoporosis, disc degeneration, fractures, and lumbago.

< Commentary >Estimated prevalence rates of current smoking in patientswith pain ranged from 42 to 68%, which may be up to twicethat observed in the general population (including patientswith non-chronic pain and healthy individuals) [26]. The
prevalence rates of chronic pain in former smokers (35–49%)
were higher than in nonsmokers, irrespective of age and sex[26]. In addition, chronic pain was more severe in smokers
than in nonsmokers and former smokers, as measured bypain frequency, intensity, duration, and total number of pain
sites [27].
Regarding the prevalence of nociceptive pain, a largescale cohort study reported that smoking was associatedJournal of Anesthesia

with a 20% increase in the risk of musculoskeletal pain
(odds ratio [OR]: 1.23) [28]. Moreover, the prevalence ofchronic pain symptoms such as spinal pain, fibromyalgia,
and head pain was also higher in women who smoked daily
than in nonsmoking women (OR: 2.04) [29]. The odds ofdeveloping rheumatoid arthritis were approximately twice ashigh in current smokers than in nonsmokers, and four times
higher in rheumatoid factor–positive current smokers [30].
Regarding pain severity, studies on spinal and temporomandibular pain reported significantly higher visual analogue
scale (VAS) pain scores in smokers than in nonsmokers,
and heavy smokers had a significantly greater risk of rheumatoid factor–positive rheumatoid arthritis than nonsmokers(OR: 3.06) [31–33]. Previous studies generally indicated thatsmoking was associated with higher levels of inflammatory
nociceptive pain, irrespective of whether the pain sensitivity
was measured using the VAS, a numerical rating scale, orother methods.
The odds of experiencing neuropathic pain were also
higher in smokers than in nonsmokers (e.g., postherpetic
neuralgia OR, 1.62–2.08; sciatica OR, 2.01), and current
or former smoking status was significantly associated withintense or very intense pain at the onset of herpes zoster(OR: 2.00) [34, 35].
Although our literature search did not identify studies
that investigated smoking-related psychosocial pain using
the VAS, a numerical rating scale, or similar scales, it isreasonable to believe that smoking increases the prevalence
and intensity of psychosocial pain because smoking exacerbates psychological problems, as described below. Social
environmental factors, such as family and personal history,
occupational functioning, and social support, play an important role in the cause, course, and outcomes of pain andsmoking [26]. Lower socioeconomic status and educational
levels were also independently associated with greater pain
and increased cigarette consumption [26].
Moreover, current and previous smoking was an independent predictive factor of the prevalence and intensity ofchronic pain (e.g., neuropathic, facial, temporomandibular,
and abdominal) [27].
Research using functional magnetic resonance imaging
showed that smoking altered brain functional connectivityof the basal ganglia, resulting in pain chronification [36].
A longitudinal study showed that current smoking status
at baseline was an independent predictor of chronic pain
persisting for ≥ 10 years (OR: 1.43) [37]. Moreover, a significant dose–response relationship was observed between
smoking and chronic pain intensity [38].
Compared with their nonsmoking counterparts, smoking patients with pain were at greater risks of mental healthproblems (anxiety, depression, catastrophic thinking), sleep
problems (daytime fatigue, somnolence, poor sleep quality),
abuse of alcohol and other substances, and suicidal ideation[39, 40]. Smoking may also delay the recovery of physicalabilities such as daily walking and fine upper-limb motor
skills, which may interfere with post-injury employment andsocial life [41–43].
Furthermore, smoking was associated with changes tothe bone and surrounding structures, increasing the lifetime
risks of developing osteoporosis, disc degeneration, fractures, and low back pain [44, 45].
Is passive smoking associated with pain?
< Summary Statements >• Passive smoking increases postoperative pain intensity.
• Passive smoking increases the prevalence of chronicpain.

• Passive smoking aggravates disc degeneration and low

back pain.

• Passive smoking in pregnant women is associated withthe development of hyperalgesia in their infants.

< Commentary >Among patients who underwent open lobectomy surgery,those exposed to secondhand smoke had significantly lower
postoperative arterial oxygen tension than nonsmoking controls, and required larger amounts of morphine consumption [46]. In patients undergoing abdominal hysterectomy,
passive smoking was associated with greater postoperative
VAS pain intensity scores and larger doses of fentanyl-based
patient-controlled analgesia compared with nonsmoking[47].
In a retrospective population-based study in Denmark,both active and passive smoking were associated with higher
prevalence rates of back pain and other types of chronic pain[38]. In a prospective study of children undergoing venous
catheterization, passive smoking increased intraoperative
pain perception [48]. A cohort study in Hong Kong showedthat passive smoking, particularly in public outdoor places,
was associated with lower physical and mental health scores,
including body pain [49].
Studies in humans [50] and animals [51, 52] showed that
passive smoking elevated the risk of disc degeneration. In
a prospective cross-sectional study of female high school
students, passive smoking was associated with the incidenceof low back pain during the previous month [53]. Of note,however, a retrospective epidemiological study that examined the relationship between nonspecific low back pain andenvironmental and life-style factors in children aged 7.5 to
14 years did not identify passive smoking as a significant
etiological factor [54].

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In a cohort study of passive smoking in Singapore, theprevalence of teething pain in infants was significantly
associated with their mothers’ exposure to passive smoking
during early pregnancy [55]. Another study reported that
intrauterine exposure to tobacco smoke was associated withthe pain perception levels of newborns, as determined during
routine vaccination injections given at 48 h after birth [56].
These findings suggest that passive smoking in pregnant
women affects the pain perception of their infants.

< Summary Statements >smoking cessation because they generate nicotine-containing
vapors that are free from harmful substances resulting fromcombustion or heating of tobacco leaf. However, the US
Centers for Disease Control and Prevention has warned thate-cigarettes can cause serious acute lung injuries, termed“e-cigarette or vaping product use associated lung injury”(EVALI), and suggested that these injuries are attributable
to tetrahydrocannabinol (a psychoactive ingredient in marijuana regulated in Japan), cannabidiol (CBD), and vitamin E
acetate present in e-liquids. In Japan, CBD-containing products are available for use in e-cigarettes and HTPs, warranting close attention. E-cigarette products that are marketedin Japan do not contain nicotine, and thereby appear to have
low efficacy for smoking cessation [63].

• Heated tobacco products (HTPs) should be treated in theDoes smoking influence postoperative pain?

Do novel tobacco products influence pain in patients?

same way as conventional cigarettes because they contain
nicotine, which increases pain sensitivity.

< Commentary >HTPs release tobacco components by directly heating
tobacco leaf or passing vaporized glycerol or other solvents
over tobacco leaf. From the perspectives of tobacco andnicotine regulations in Japan, they are completely different
from nicotine-containing electronic cigarettes (e-cigarettes),
which are gaining increasing popularity overseas. Nicotine
is classified as a pharmaceutical agent in Japan under the
Pharmaceuticals and Medical Devices Act (Act on Securing
Quality, Efficacy and Safety of Pharmaceuticals, Medical
Devices, Regenerative and Cellular Therapy Products, Gene
Therapy Products, and Cosmetics). Currently, nicotine-containing e-cigarettes are not commercially available in Japan.
HTPs release aerosols containing nicotine at concentrations that differ from one product to another [57, 58]. Controlled confinement studies showed that plasma nicotine levels on the fifth day of confinement were comparable between
HTP users and cigarette smokers [59].
Several reports have been published regarding the relationship between e-cigarette use and pain. Compared tosmokers who reported no pain in the past 2 weeks, thosewith significant pain were 3 times more likely to use e-cigarettes and a greater number of nicotine products, and wereapproximately 4 times more likely to have tried e-cigarettes
and 7 times more likely to have tried cigars [60]. A studyof e-cigarette users showed that pain experience was related
to the severity of their e-cigarette dependence and to theirperceived barriers to quitting e-cigarettes [61].
In a population survey conducted in the United States, asubstantial increase in e-cigarette use was associated witha significant increase in smoking cessation rate [62]. Some
may argue that nicotine-based e-cigarettes provide a typeof nicotine replacement therapy, and thereby contribute to13< Summary Statements >Recommendation: We strongly recommend smoking cessation because smoking is a significant risk factor for poor
control of acute postoperative pain. [1C].
• Nicotine administration has only negligible effects onalleviating acute postoperative pain.

• Smokers show higher acute pain intensity scores post-

operatively than nonsmokers, and require greater opioid
analgesic doses. These trends are more pronounced withhigher levels of nicotine dependence.
• Patients show lower postoperative acute pain scores whenstarting smoking abstinence ≥ 3 weeks before surgery
than when starting it immediately before surgery.
• Smokers are at greater risk than nonsmokers for chronic
postoperative pain and long-term use of opioids and otheranalgesics.
< Commentary >Based on evidence of generally low quality, a Cochranereview of acute postoperative pain reported that nicotine
formulated as a nasal spray or transdermal patch could
reduce pain scores at 24 h postoperatively compared withplacebo, but the effects were relatively small (0.88 points
on a 0–10 pain scale) [20]. Nicotine has limited effects onacute postoperative pain relief. In a prospective study ofpatients undergoing elective surgery under general anesthesia, male current smokers had worse VAS pain intensity
scores postoperatively and required larger opioid doses thanmale nonsmokers and former smokers [64]. In a meta-analysis that investigated the causes of poor acute postoperative pain control based on 33 clinical studies, preoperativesmoking was an independent predictor [65]. The Table 1

Journal of Anesthesia
Table 1  Effects of smoking on acute postoperative pain intensity
Procedure
Locomotor

Head and neck
Chest
AbdomenIncreased acute pain score
Rotator cuff repair
Hip replacement
Knee replacement
Foot and ankle surgery
Orthopedic surgery in general
Thyroid and parathyroid surgery
Otolaryngological surgery
Thoracoscopic surgery
Thoracic surgery
Distal gastrectomy
Hepatectomy
Gynecologic pelvic surgery

summarizes other studies that demonstrated the impact ofsmoking on acute postoperative pain intensity or opioid
analgesic requirements in patients undergoing a variety ofsurgical procedures.
In a study by Yu et al. of patients undergoing thoracic
surgery, postoperative pain severity and patient-controlled
intravenous sufentanil requirement increased with increasing nicotine dependence [74]. In patients with high nicotine
dependence who had radical resection of lung cancer, preoperative smoking cessation within 3 weeks of surgery resulted
in worse postoperative pain outcomes and greater opioid
requirement than earlier smoking cessation [78]. Even
those who stopped smoking ≥ 3 weeks before surgery had
worse postoperative pain intensity scores and greater opioid
requirements than nonsmokers. These findings underscore
the need for a sufficient duration of smoking abstinence
before surgery to minimize the adverse effects of smoking.
Smokers are at greater risk of not only acute postoperative pain but also of chronic pain ≥ 3 months after surgery.
Smoking was associated with the development of chronic
pain after breast surgery [79], and it increased pain intensity scores at 15 months postoperatively [80]. Smoking was
also associated with chronic postoperative pain in patientstreated with hysterectomy [81], total shoulder arthroplasty[82], and nonunion surgery [83]. Moreover, smoking was
associated with opioid analgesic use for ≥ 3 months postoperatively in various orthopedic surgeries, including hip
replacement [84], shoulder arthroplasty [82, 85], and spine
surgeries [86, 87], as well as in cardiothoracic [88], urologic[89], and kidney donation surgeries [90]. Smoking is a significant predictor of opioid abuse [91, 92].
The "Practical Guide for Perioperative Smoking Cessation” published by the Japanese Society of Anesthesiologists
states that smoking is associated with various postoperative
respiratory and other complications such as delayed wound

Cuff et al. [66]Buzin et al. [67]Sun et al. [73]Yu et al. [74]Shen et al. [76]Increased opioid analgesic dose

Wojahn et al. [68]Mulligan et al. [69]Steinmiller et al. [70]Chen et al. [71]Dang et al. [72]Yu et al. [74]Kim et al. [75]Shen et al. [76]Woodside [77]healing and surgical site infection, and strongly recommends
preoperative smoking cessation to reduce perioperative risks[93] (evidence level: B).
The recommendation was based on the result of systematic review and meta-analysis [65]. The overall quality ofevidence is low because of a risk of bias and the indirectness of the results. The desirable effects of smoking cessation clearly outweigh the undesirable effects. Therefore, westrongly recommend smoking cessation because smoking isa significant risk factor for poor control of acute postoperative pain. [1C].
Does smoking affect cancer‑related pain?
< Summary Statements >• Cancer-related pain increases when patients continue tosmoke after being diagnosed with cancer.

• Cancer patients who smoke have a greater need for opioid

analgesics after surgery than nonsmoking patients, andare more prone to pain chronification.
• Smoking increases the prevalence of chemotherapyinduced peripheral neuropathies.
• Smoking increases the incidence of painful side effectsof cancer radiation therapy.
• Among patients with advanced cancer, smokers show
higher pain intensity scores and require larger doses of
opioid analgesics than nonsmokers.
< Commentary >Smoking increases preoperative and postoperative painin cancer patients undergoing surgery. It also increases pain

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in patients receiving chemotherapy and radiation therapy.
Moreover, it increases pain in patients with advanced cancer.
Some studies have reported that smoking cessation lowers
pain intensity.
Multiple observational studies showed that patients
who continued to smoke after cancer diagnosis had more
severe pain than nonsmokers and former smokers [94, 95].
In addition, smoking that continued after cancer diagnosis
increased the likelihood of pain treatment [96]. One crosssectional study and one small-scale cohort study indicatedthat smoking cessation after cancer diagnosis reduced pain[97]. Regarding the relationship between cancer pain andpre- and postoperative smoking, nonsmokers had less opioid consumption in the immediate postoperative period [78,98], while smokers experienced greater chest and wound
pain as well as a persistent decrease in physical and social
functioning postoperatively [99]. Since nonsmokers had ahigher postoperative quality of life (QOL) [99], patients
undergoing surgery should be smoke-free to minimize thepostoperative risks of pain chronification and functional
impairments.
In patients undergoing radiation therapy or chemotherapy, smoking is associated with greater incidences of side
effects and elevated levels of pain. Specifically, smoking is
an identified risk factor for chemotherapy-induced peripheral neuropathies [100], oral pain due to mucositis and otheradverse events in oral cancer patients undergoing radiation
therapy [101], and severe skin toxicities in breast radiation
therapy [102, 103].
Among patients with advanced cancer, smokers reported
significantly higher degrees of pain, fatigue, anorexia,
depression, anxiety, and insomnia than nonsmokers, andrequired larger doses of opioid analgesics [104, 105]. Smokers with advanced cancer had a lower QOL due to stronger
pain intensities [106].

Effects of smoking on pain (pain treatment)< Commentary >Smokers require greater opioid doses for pain relief
than nonsmokers, but despite their higher doses, they show
greater pain intensity scores. This is the case for both acuteand chronic pain, including acute postoperative pain [78]and chronic low back pain [107]. In a study of hydrocodone
use in patients with chronic pain, smokers required larger
doses but had less successful pain control and lower serumhydrocodone levels than nonsmokers [107]. In studies of
duloxetine in smoking and nonsmoking psychiatric patients(not directly related to pain relief), serum levels of the drug
were lower in smokers than in nonsmokers, suggestingthat tobacco smoke components induce drug-metabolizing
enzymes (e.g., cytochrome P450 1A2) [108, 109]. In a studyof chronic pain medication use, smokers showed poor pain
medication adherence, and overuse was associated with current smoking [110]. Smokers had a greater likelihood of
long-term opioid use after major surgeries [86, 111].
Smokers showed poorer outcomes of non-pharmacologic
pain interventions such as nerve block [112] and spinal cord
stimulation [113]. They also showed less satisfactory outcomesthan nonsmokers in spinal surgery [114, 115] and arthroplasty[116] in terms of pain relief, patient satisfaction, and QOL.
Smokers were at greater risk of undergoing revision total knee
arthroplasty [117]. Moreover, multidisciplinary pain treatment
programs yielded lower completion rates [118] and lower rates
of return to work [119] in smokers than in nonsmokers. Smokers
generally have more difficulty controlling pain than nonsmokers.
Daily tobacco smokers often experience greater painwith short periods of smoking deprivation [14]. Smoking is
considered one of the factors that complicate pain management. Given that pain intensity ratings were positively correlated with the severity of nicotine withdrawal symptoms[15], controlling these symptoms is important not only insmoking cessation interventions but also in pain relief care.
Smokers will benefit from cessation interventions that are
tailored to meet their specific conditions.
Is smoking involved in opioid‑related problems?

Can pain be effectively managed in smoking patients?
< Summary Statements >• Smokers are more likely to exhibit poor medication

adherence and overdose than nonsmokers.
• Pain treatment outcomes are poorer in smokers than in
nonsmokers.
• Smokers show poorer outcomes of multidisciplinary pain
management and lower rates of return to work.
• Smoking interferes with effective pain control because
pain worsens even after short periods of smoking deprivation.

13< Summary Statements >• Opioid analgesic use is more prevalent in smokers than

nonsmokers.

• Opioid analgesic consumption is higher in smokers than

nonsmokers.

• Smoking is more common in patients with opioid use

disorders than patients without.

• Young smokers have higher rates of opioid analgesic use

and increased risk of opioid use disorder.

• Opioid analgesics do not reduce a risk of withdrawal

symptoms after smoking cessation.

Journal of Anesthesia< Commentary >Since both tobacco and opioid analgesics are dependent
substances that activate the brain reward system, the use of
opioid analgesics in current or former smokers is often a
topic of scientific discussions. Previous reports indicatedthat smokers had more high risk for prevalence rates of opioid analgesic use [120–122], opioid analgesic use consumption [84, 111, 123, 124], and opioid use disorders [104, 122,
124, 125], compared with nonsmokers.
Therefore, it is important to explain and educate aboutsmoking cessation to smokers, in order to minimize theamounts of opioid analgesics in patients requiring pain
relief.
In addition, if prescribing opioid analgesics for pain relief
is considered, a more careful approach, including the indication of opioid analgesic use, will be needed, in order toprevent opioid analgesic misuse and transition to opioid use
disorder. Risk factors for opioid use disorder among primarycare patients include smoking history at a young age, unemployment, multiple drug use [121, 122, 126], and cancer
pain [104].
Since both smokers with and without opioid use disorder
showed similar degrees of withdrawal symptoms of smoking
cessation [127], it should be assumed that opioid analgesics
do not reduce nicotine withdrawal symptoms.

Impact of smoking cessation on pain sensation(significance of therapeutic intervention)
Does smoking cessation help improve pain?
< Summary Statements >Recommendation: We strongly recommend smoking cessation interventions to help improve chronic pain. [1C].
• Smoking cessation helps alleviate pain by preventing

exacerbation of underlying causes.

• Nicotine withdrawal symptoms arising from smoking

deprivation may temporarily elevate pain sensitivity.

• Although smoking cessation can reduce pain and improve

responsiveness to pain treatment in patients with certain
types of disease, it is not clear whether smoking cessation
provides positive short-term pain relief benefits in a wide
spectrum of patients with chronic pain.

< Commentary >Smokers experience more severe musculoskeletal andother chronic pain than nonsmokers because smoking causes
tobacco-related diseases; damages musculoskeletal and othersystems, leading for instance to osteoporosis, lumbar discdisease, and delayed bone and wound healing; and induces
neuronal changes in pain pathways [11]. However, smoking
cessation was not identified as an independent predictor ofpain symptom changes in many studies [128, 129]. Chronic
pain patients who smoke often fail to experience pain relief
when they stop smoking. This is partly because they use
tobacco as a means to cope with stress and depression, andhence nicotine withdrawal increases their pain perception.
Tobacco smoking has acute analgesic effects that interferewith smoking abstinence efforts [10]. By contrast, studies inseveral clinical settings found that patients who quit smoking
reported significantly greater improvements in pain and significantly better responses to treatment [32, 130]. Altogether,
the available evidence does not allow us to definitively conclude that smoking cessation readily alleviates chronic pain.
However, smoking cessation obviously can help suppress theaggravation and progression of tobacco-related diseases andother pain-causing pathologies, and its long-term benefits
are undeniable. Therefore, it is the responsibility of pain
practitioners to determine how they can help improve theirpatients’ pain-causing conditions and their healthy and overall life expectancy. To this end, they should share available
evidence with their patients to decide on optimal pain anddisease control strategies. Pain practitioners and smoking
cessation therapists should develop patient awareness andeducation programs and treatment protocols to help patientsachieve pain alleviation, complete freedom from smoking,and other goals.
The recommendation was based on the result of systematic review and meta-analysis [128]. The overall quality ofevidence is low because of the imprecision and inconsistency of the results. The desirable effects of smoking cessation clearly outweigh the undesirable effects. Therefore, westrongly recommend smoking cessation interventions to help
improve chronic pain. [1C].
Can freedom from smoking be achieved in patientswith pain?
< Summary Statements >• Patients with pain are often refractory to smoking cessa-tion interventions due to high nicotine dependence andpsychiatric/psychological complications.
• Patients with pain require intensive interventional programs that include pain relief care, education emphasizing that smoking does not reduce pain, and assistance in
coping with anxiety.

13

Journal of Anesthesia< Commentary >Nicotine provides acute analgesic effects [10]. Consequently, smoking patients tend to use tobacco to relieve
or avoid pain [11, 131]. Repeated use of tobacco to avoid
pain increases the risk of nicotine dependence. In addition,
patients with pain are anxious about recurrence and exacerbation of pain. This anxiety triggers smoking behavior, further increasing the risk of nicotine dependence. Pain patients
who smoke tend to experience depression and have difficulty
and low confidence in their ability to quit or remain abstinent[132–134]. These findings indicate that pain patients who
smoke are refractory to stop-smoking treatment.
In smoking patients with pain, abstinence interventions
should start by addressing their pain because persistent
pain is one of the main reasons for abstinence failure.
Patients reported greater interest in receiving cessationinterventions after initiating treatment for chronic pain[135], and pain ratings prior to smoking cessation were auseful predictor for the risk of early smoking relapse [136].
Pain control is a key to successful smoking cessation insmokers with pain.
Patients should learn that smoking does not reduce pain.
The expectation that smoking would help cope with pain
predicted lower odds of abstinence [137]. In a randomized
controlled study of laboratory-induced pain, participants
reported a reduced urge to smoke when they were challenged about their idea that smoking would decrease pain[138].
Pain-related anxiety was significantly associated withsmoking dependence measures, and was an independentrisk factor motivating smoking behavior [139, 140]. For
these reasons, pain-related anxiety should be addressed insmoking cessation interventions for patients with pain.
Pain patients who smoke are likely to become highly
nicotine dependent because they use tobacco as a means
to cope with their pain and anxiety [132, 133]. Therefore,
they should undergo interventions that are more intensive
than standard smoking cessation programs. Multidisciplinary smoking cessation programs that are specificallydesigned to address patients’ psychiatric problems, mobility, and daily activities may be necessary [134]. Given
the finding that craving for cigarettes was significantly
associated with pain intensity ratings [15], pharmacologic treatments, including smoking cessation aids, arerecommended.
Smokers with chronic pain have been reported to show
higher prevalence rates of mobility and activity impairments[134, 141, 142]. For patients with severely hindered mobility, cessation interventions in the form of over-the-phonecounseling, telemedicine, and mobile applications can be
an effective option.

13

Do smoking cessation aids contribute to smoking cessationin patients with pain?
< Summary Statements >Recommendation: We strongly recommend the use ofsmoking cessation aids to help pain patients quit and stayquit. [1B].
• In smokers with chronic pain, nicotine withdrawal

increases pain intensity and reduces the likelihood of
abstinence. Therefore, the use of smoking cessation aids
is advised.

< Commentary >Smokers with chronic pain use a larger number of cigarettes per day and are more likely to become nicotine dependent than those without chronic pain. If they have previously
experienced difficulties when trying to stop smoking, severe
nicotine withdrawal symptoms will probably develop on theirnext attempt [133]. Patients with chronic pain are resistantto smoking cessation treatment because pain intensities are
positively correlated with desire to smoke [143]. Therefore,smoking cessation interventions should include effective pain
control measures [144]. As smokers with chronic pain are
amenable to using pharmacotherapy for smoking cessation[145], physicians should consider pharmacologic treatments
to prevent nicotine withdrawal symptoms. Under the Japanese National Health Insurance System, smoking cessation
programs cover cigarette smokers and HTP users.
First-line pharmacologic therapies for smoking cessation include nicotine replacement therapy (NRT), the partialnAChR agonist varenicline, and bupropion sustained release(an antidepressant that inhibits noradrenaline and dopamine
reuptake). Various types of NRT (gum, transdermal patch,
nasal spray, inhaler, sublingual tablets/lozenges) [146] andvarenicline [147] can help improve the success rate of smoking cessation. In Japan, nicotine patches, nicotine gum, andvarenicline have been approved for marketing.
It is unknown what types of smoking cessation aids aremost effective in patients with chronic pain. One pilot study
provided preliminary data suggesting the positive detoxification effects of varenicline in opioid-dependent adults withchronic pain, despite the absence of improvements in pain
severity and depression [148]. In a study using murine pain
models, varenicline demonstrated antinociceptive effects,
indicating its potential as a treatment for chronic pain disorders [149]. A Cochrane review was conducted regarding
antidepressants’ smoking cessation effects, and showedJournal of Anesthesia

that bupropion sustained release and nortriptyline significantly increased success rates [150]. A placebo-controlled
crossover study reported that bupropion sustained release(150–300 mg/day) effectively improved neuropathic pain[151], but this product has not currently been approved
for marketing in Japan. Nortriptyline is often prescribed inJapan for treating pain. Its pain-relieving effects may highlight its utility as a smoking cessation aid. Considering that
serotonin noradrenaline reuptake inhibitors may have fewerside effects than other types of antidepressants, they may
be useful as smoking cessation aids in patients with pain,
particularly those with diabetic peripheral nerve disorders
and lumbago. Future research is warranted.
Other important components of smoking cessation interventions for smokers with chronic pain include stress mitigation during pain treatment and careful management ofprescription opioids [152]. Moreover, given the importanceof pain physicians advising and assisting patients to quit
smoking in their practices, an educational module aboutsmoking and pain should be incorporated in pain medicine
training programs [153].
The recommendation was based on the previous Cochranesystematic reviews [146, 147]. The overall quality of evidence is moderate because of indirectness of evidence (nostudy in patients with chronic pain context). The desirable
effects of smoking cessation aids clearly outweigh the undesirable effects Therefore, we strongly recommend the use ofsmoking cessation aids to help pain patients quit and stayquit. [1B].
Does cognitive behavioral therapy (patient education)
assist smokers with pain?
< Summary Statements >• Multidisciplinary pain management programs that

include cognitive behavioral therapy (CBT) can beapplied to smoking cessation treatment.
• Behavioral therapy including smoking cessation in combination with physical therapy can be a first-line intervention for patients with chronic pain.
< Commentary >Many patients with chronic pain have difficulty quitting
smoking. However, CBT can help increase the odds of quitting, allowing them to complete multidisciplinary pain treatment at a higher success rate. Therefore, integrating CBTbased smoking cessation interventions into pain therapy canbe an effective treatment program for smokers with chronic
pain [154].

On the other hand, a systematic review of smoking cessationinterventions for patients with chronic pain, including pharmacologic treatments, physical activity programs, and behavioral and psychological therapies, suggested that they could
possibly change the smoking status and reduce the number ofcigarettes consumed per day, but albeit with no effects on pain,
physical function, depression, or anxiety [128]. Moreover, ina randomized controlled study that compared standard andindividually tailored intensive smoking cessation programs inpatients with rheumatoid arthritis, both programs reduced themean number of cigarettes smoked per day (despite the absenceof significant differences between programs in quit rate, pain
intensity, physical functioning, mood, and QOL) [155].
These findings suggest the utility of CBT-based multidisciplinary pain treatment programs in assisting with smoking reduction. However, the patients with chronic pain often
rely on smoking as a means to cope with pain and distress,
and a large proportion of patients who use opioid analgesics for pain relief report that opioid consumption stimulates
smoking. Important barriers to making a quit attempt during pain treatment included making changes in opioid dose
while quitting and perceived difficulty managing multiple
treatment-related stressors [152].
Under these circumstances, behavioral therapy for behavioral change including smoking cessation either independently orin combination with physical therapy, can be a first-line intervention for patients with chronic pain [156] (for more details,
refer to the next section). CBT can be effective for pain management and smoking cessation. However, its effectiveness for
smoking cessation in patients with pain and managing pain insmoking patients must be confirmed in future studies.
Does exercise therapy (physical exercise and activity
programs) assist smokers with pain?
< Summary Statements >• Exercise-induced hypoalgesia (EIH) is mediated by thebrain reward system in a manner similar to nicotineinduced acute analgesia. However, EIH is not addictive,
and provides promising long-term effects.
• Smoking cessation and physical exercise both improvedisease activity, physical function, and QOL, whereassmoking interferes with pain rehabilitation effects.
• Physical inactivity, smoking, and other unhealthy lifestyle factors increase the risks of chronic pain.
• Lifestyle management programs that encourage smoking abstinence, physical exercise, and other behavioral
changes, administered either alone or in combination
with conventional physical therapy, can be a first-line
intervention for patients with chronic pain.

13

Journal of Anesthesia< Commentary >Nicotine has acute analgesic potential [11]. It activates
both nAChRs and opioid receptors, which trigger the
release of dopamine in the nucleus accumbens, the brain’s
reward center (nicotine reward system). This process issimilar to the mechanism of EIH. However, EIH evidently
provides much more effective and healthier effects on pain
control than smoking. Long-term adherence to exercise
regimens can help improve pain control, physical function, and QOL in patients with chronic pain. A majordifference between EIH and nicotine-induced analgesia
is that EIH results in mostly endogenous pain modulation whereas nicotine absorbed from smoking serves as
an exogenous agonist. This and other differences makephysical exercise less addictive. In a study of smoking
cessation in patients with ankylosing spondylitis, smoking
cessation interventions significantly lowered disease activity and pain intensity, and increased physical functioning
and QOL [130]. These findings indicate that smoking cessation can yield favorable health benefits similar to thoseof physical exercise. Moreover, in a study of patients withchronic spinal disability undergoing an intensive functional chronic pain management rehabilitation program,the percentages of patients who completed the program
and those who retained work at 1 year post-treatment
decreased with smoking levels, although no significant
differences were noted in other socioeconomic outcomesat 1 year post-treatment [157]. Smokers reported slightly
higher post-treatment pain and disability ratings. These
results provided evidence that smoking negatively affects
pain rehabilitation effects.
Pain is strongly associated with physical inactivity, smoking, and other unhealthy lifestyle patterns. Heavy-smoking
individuals who were physically inactive tended to havegreater odds of smoking when experiencing pain [26]. Individuals with chronic low back pain tended to have lower
physical activity during leisure time and a higher body massindex [158]. Smoking, lack of exercise, physical inactivity,and other negative lifestyle patterns were risk factors forlumbago [159]. In addition, persistent chronic widespread
pain was weakly associated with former smoking and overweight, although not with moderate exercise or alcohol use[28]. These results are consistent with those of another study
reporting that smoking and other negative lifestyle factors
were risk factors for chronic widespread (musculoskeletal)
pain [160]. Given the inverse relationship between chronic
pain (e.g., low back pain) and positive lifestyle behaviors
such as smoking cessation and physical activity, behavioral
change (lifestyle management) interventions that include
smoking cessation support, administered alone or in combination with physical therapy, can be a first-line option forpatients with chronic pain. They will also reduce the socioeconomic burden of chronic pain [156].

13

Appendix
Search Formulae (July 2020)
MEDLINE (PubMed)
Keywords: “smoking,” “tobacco,” “smoking prevention,”“smoking cessation,” “smoking cessation aid,” “nicotine,”“tobacco use disorder,” “analgesia,” “analgesic,” and “pain.”

Literature search was conducted in July 2020 using
the following formulae:#

Search Formula

Results

1“Smoking Cessation” [MeSH] OR “Smoking Reduction” [MeSH] OR “Tobacco Use Cessation” [MeSH]“Smoking Prevention” [MeSH]“Smoking” [MeSH] OR “Tobacco Use” [MeSH]“Tobacco Use Cessation Devices” [MeSH]“Smoking Cessation Agents” [MeSH]
Nicotine [tiab]“Tobacco Use Disorder” [MeSH]
or/#1–#7
analges* [tiab]
analgesia [MeSH]
analgesics [MeSH]“Acute Pain” [MeSH] OR “Chronic Pain” [MeSH] OR“Cancer Pain” [MeSH]
or/#9–#12
8 and 13
Filters: from 2000 to 2020

29,458

2
3
4
5
6
7
8
9
10
11
12
13
14
15

17,979147,867
1800
148
41,047
11,169194,066
129,715
43,859190,769
17,208298,420
2003
1446

Declarations
Conflict of interest Hiroki Iida: Shionogi Pharmaceutical Co., Ltd.
(scholarship donation ¥1,200,000). Yoko Sugiyama: Pfizer Inc. (application grant US $44,536.96), Japan Agricultural Cooperative (funded
course ¥18,000,000). Shigeki Yamaguchi: Daiichi Sankyo Co., Ltd.
(Per diem allowances (e.g., lecture fees) ¥1,117,573), Hisamitsu
Pharmaceutical Co., Inc. (Per diem allowances (e.g., lecture fees)¥1,128,298).
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as longas you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
were made. The images or other third party material in this article areincluded in the article's Creative Commons licence, unless indicatedotherwise in a credit line to the material. If material is not included in
the article's Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you willneed to obtain permission directly from the copyright holder. To view acopy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/.

Journal of Anesthesia

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