FormalPara Key Summary Points

The effect of smoking on pain is complex: while chronic tobacco use is associated with a higher rate of chronic pain, nicotine has analgetic properties.

Little is known on the effect of smoking cessation on pain perception.

Our systematic reviews assessed 13 clinical studies on pain after smoking cessation.

Most studies showed that cigarette withdrawal leads to a phase of decreased pain tolerance and increased pain intensity.

Our results warrant increased attention and care for pain management among patients in the acute phase of nicotine withdrawal.

Introduction

Tobacco is the most widely abused substance and the leading cause of morbidity and mortality, with 1.3 billion adult smokers globally in 2020 [1,2,3]. Furthermore, smoking is one of the best-studied risk factors for cardiovascular diseases [1, 4, 5], several types of cancer [6,7,8], infections [9], and diseases associated with maladaptive immune responses [10]. In addition, smoking is a well-known risk factor for acute and chronic pain [11, 12]. For example, chronic low back pain occurs more frequently in smokers than in the normal population due to reduced blood supply to the intervertebral discs and associated degenerative changes [13]. Similarly, smokers are more likely to be affected by knee pain due to cartilage defects, and decreased cartilage substances are associated with a positive smoking history [14]. Recent evidence also presents smoking as a risk factor for cluster headaches [15]. Furthermore, smokers experience more pain and functional limitations regardless of the disease than nonsmokers [16].

At the same time, acute pain often triggers the craving for cigarette consumption, resulting in a positive feedback mechanism [17]. There are over 9000 chemical substances in tobacco smoke, of which nicotine is the most psychoactive substance and most strongly associated with the development of addiction [18]. Some studies show that nicotine has a transient analgesic effect. This effect could be influenced by gender, type of pain stimulus, and nicotine dose [16]. While constant analgesic effects can be demonstrated with conditioned pain modulation, no difference in pain tolerance is apparent with heat or electrical stimuli. Systemic nicotine administration also reduces postoperative pain, as demonstrated in several studies [19,20,21]. These results highlight the positive feedback mechanism of nicotine—smoking reduces acute pain, positively reinforcing smoking behavior [16].

In addition to a direct analgesic effect of nicotine via agonism at nicotinic acetylcholine receptors (nAChR) [22], it may influence pain perception through the endocrine system, more specifically by activating the hypothalamic–pituitary–adrenal axis. Physiologically this may occur during stressful situations and can increase pain threshold as well as decrease pain sensitivity [23]. Nicotine also leads to activation of the axis, but long-term use leads to desensitization and the development of tolerance [16].

Although the role of smoking on the pathophysiology of acute pain has been well researched and extensively reviewed [16, 24,25,26,27,28,29,30,31], the effect of tobacco withdrawal on pain-related outcomes is yet to be thoroughly investigated. Several studies show a decrease in pain perception after sustained tobacco withdrawal [32, 33]; at the same time, there is evidence of reactively decreased pain tolerance during the early stages of abstinence [17]. This characteristic has implications for several areas of medicine. For instance, among patients with short-term tobacco abstinence undergoing surgery, a change in pain tolerance may result in increased pain and a lower quality of postoperative recovery [34]. Given such broad implications of changes in pain-related outcomes with smoking cessation, this systematic review aims to evaluate whether a period of decreased pain tolerance and increased pain intensity occurs with smoking cessation.

Methods

A systematic literature search was conducted for controlled studies investigating the influence of smoking cessation on acute and postoperative pain in PubMed and Web of Science databases. The search strategy combined terms for smoking and study designs with expressions for pain that have been previously described [35] and are summarized in Table 1. Furthermore, this study’s protocol was published and is accessible from the Open Science Foundation Registries [36].

Table 1 Search strategy
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Potentially relevant literature identified during our initial search was imported into the web app “Rayyan QCRI” for the screening process after removing duplicates. Two reviewers (T.L., K.L.I.) independently screened the literature, with a third reviewer (H.B.C.) mediating in case of conflicting decisions. Acute pain was defined as the duration since the onset of pain of no more than 3 months, including but not limited to postoperative pain and experimental pain models. The population of interest included male and female smokers. Smoking cessation interventions were defined as all interventions aimed at smoking abstinence. The outcome was defined as pain-relevant parameters (pain perception threshold, pain tolerance, and pain intensity) and postoperative opioid requirements. In case of missing data in the original reports, authors were contacted with a request for providing unreported data. The studies were included from 1970 to 2022. The latest literature search was conducted in July 2022.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Results

The search strategy yielded 1478 papers, of which 1402 were excluded after title screening and another 63 subsequently excluded after the abstract screening. Finally, 13 studies meeting our inclusion criteria were selected for full-text screening. A flowchart of the study is shown in Fig. 1. The details of the studies are summarized in Table 2.

Fig. 1
figure 1

Flowchart of the screening process

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Table 2 Study characteristics
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Only two studies were designed as randomized controlled trials; five are nonrandomized trials. Six studies are cohort studies. The included studies collectively represented data four countries: the USA (n = 8), China (n = 3), Pakistan (n = 1), and the Republic of Korea (n = 1). The oldest study was published in 2000 [34], and the rest were published between 2004 and 2021 [3, 17, 37,38,39,40,41,42,43,44,45,46].

The collective study population included 1721 participants. Overall, 43.3% of the included individuals were females. Three studies presented data exclusively from males [41, 45, 46], one from females [34], and one did not report gender outcomes [44]. One paper dealt with pain in adolescents aged 14–18 years [37], while the remaining dealt with adult patients, some without age limitations [38, 43]. The mean age of the included subjects was 44.2 ± 8.2 years.

The duration of smoking cessation varied considerably. The shortest duration was 2 h [3]; others investigated the effect after more than 1 month of smoking cessation [41, 44]. Smokers had a history of 14.6 ± 9.9 years of nicotine abuse. The mean number of daily smoked cigarettes was 17.5 ± 10.3.

Different modalities were used to induce pain. Two studies investigated spontaneous pain [38, 42]; one study used a capsaicin pain model [17], and one used radiant heat pain [3]. Some studies assessed pain threshold: three assessed cold pain threshold [37, 39, 43], one heat pain threshold [43], and one electrical pain threshold [45]. Six studies investigated the effect of smoking cessation on postoperative pain levels and opioid requirement [34, 40, 41, 44,45,46]. The details of this group of studies are presented in Table 3.

Table 3 Studies in the postoperative setting
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Discussion

Our systematic literature search identified 13 clinical studies assessing pain development after smoking cessation. Most studies show that cigarette withdrawal leads to a phase of decreased pain tolerance as well as increased pain intensity. Only Cosgrove found that smoking withdrawal and the subsequent higher nicotinic acetylcholine receptors AChRs containing the b2* subunit (b2*-nAChR) availability were associated with increased pain sensitivity but not pain tolerance [39]. However, there was a high degree of heterogeneity among the examined studies regarding methodology. For instance, different pain tests were utilized, the duration of smoking cessation differed, and several different pain-related outcome parameters were considered. These factors must, of course, be considered when trying to derive generalizations. Nevertheless, some of these findings merit detailed discussion.

Outcome Parameters

Regarding outcome parameters, four studies showed a decreased tolerance to the pain test performed during smoking cessation [3, 37, 39, 43]. In addition, a decrease in the pain perception threshold was reported in three studies [39, 42, 45]. Three studies show increased pain intensity during nicotine withdrawal [17, 37, 38]. Comparing these findings led us to question whether the modality of pain influences the perception of pain during withdrawal. For example, pain triggered by cold [37, 39] seems to lead more consistently to an increased perception than heat-induced pain [43].

Time Course

The initiation timepoint for the change in pain perception after smoking cessation and the duration of the effect have immense clinical relevance. However, due to the methodological heterogeneity, only limited conclusions could be drawn. Five studies documented an increased pain perception between 12 and 48 h after nicotine withdrawal [17, 37, 38, 42, 43], while Bagot demonstrated a reduction in pain tolerance and an increase in pain intensity as early as 30 min after withdrawal among female participants, and this early onset of changes in pain perception among female participants led to a longer duration of altered pain perception [37]. Furthermore, Cosgrove demonstrated an even more significant reduction in pain perception threshold and tolerance after 7–13 days of smoking cessation [39].

Gender

The effect of nicotine on pain differs by gender. A recent review showed that nicotine generally has an analgesic effect among males but not among female participants [31]. However, whether the changes in pain perception during withdrawal vary by gender is not known. Eight of 13 studies in this review either did not report additional information on gender-specific differences [3, 17, 39, 40], or similar changes in pain perception were observed among males and females [38, 42, 43]. Four studies included only male or female participants; therefore, no conclusions could be drawn from these studies on gender-specific changes in pain perception [34, 41, 45, 46]. In the remaining two studies, both reported higher pain tolerance among male participants than female participants in the pain tests [37, 47]. Additionally, Bagot showed a change in pain perception among males after performing the cold pressor test, while female smokers showed no change during the study [37].

Postoperative Pain

Postoperative pain was the most frequently studied acute pain condition: six studies reported postoperative pain assessments and opioid requirements [34, 40, 41, 44,45,46], five investigated the need for analgesic medication [34, 38, 40, 41, 46], and five reported pain intensity [17, 33, 39, 42, 45]. One study involved pulmonary resection [46], one involved laparoscopic gastrectomy [41], one involved liver resection [45], one involved coronary artery bypass grafting [40], one pelvic/gynecological surgeries (cesarean section, vaginal, and abdominal hysterectomies) [34, 41], and one study involved scheduled noncardiac surgery [44]. These studies corroborated our hypothesis that there is an increased postoperative need for opioids after nicotine withdrawal. In addition, all six publications demonstrated a significantly higher need for analgesics among abstinent smokers.

It is worthwhile noting that two [40, 45] of these six studies compared abstinent smokers only with nonsmokers. However, nonsmokers tended to need less pain medication overall than smokers. Another two studies [41, 46] compared the effect of smoking cessation intervals of different lengths. Zhao showed that participants needed more opioids after 3 weeks of abstinence or shorter than smokers with longer than 3 weeks of abstinence [46]. Kim showed that postoperative opioid requirement decreased with increased duration of smoking cessation among patients who received fentanyl (1 µg/kg) or oxycodone (0.1 mg/kg) 30 min before the end of the surgery with postoperative intravenous patient-controlled analgesia comprising oxycodone and rescue analgesics such as ketorolac (30 mg), tramadol (50 mg), and meperidine (30 mg) [41]. Although clinical practice guidelines recommend a minimum of 8 weeks of smoking abstinence before surgery to reduce perioperative complications and smoking remission rates, this recommendation is not specific to the effects on postoperative pain [48].

Future Direction

Future studies should investigate whether an adapted pain therapy can positively influence smoking cessation. For example, Nakajima showed that smokers who perceive pain more before withdrawal have a higher risk of relapse [47]. They concluded that assessment of pain perception (e.g., by cold pressor test) could be used to identify smokers at increased risk of relapse. Furthermore, Powers concluded in their study that prolonged pain might lead to increased nicotine use, and it will be essential to investigate the benefits of pharmacotherapy to improve the control of these symptoms [49].

Likewise, it should be considered how to manage smoking cessation before elective acute pain exposures, i.e., surgery or other painful interventions. More studies on the optimal timing should be conducted.

Conclusion

Most studies examined in this systematic review show a negative influence of smoking cessation on acute pain. In addition, short-term preoperative nicotine withdrawal negatively impacts postoperative pain and postoperative opioid requirements. The currently available evidence, however, is insufficient to draw firm conclusions on the affected pain modalities, the duration of the altered pain perception, and whether male and female smokers are equally affected due to both quality (high heterogeneity) and quantity (scarcity of research in the smoking cessation pain domain) of available studies.

Our results warrant increased attention and care for pain management among patients in the acute phase of nicotine withdrawal.