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Journal of Pain & Palliative Care Pharmacotherapy

ISSN: 1536-0288 (Print) 1536-0539 (Online) Journal homepage: http://www.tandfonline.com/loi/ippc20

Opioid and : More Than Blowing Smoke

Jin H. Yoon, Scott D. Lane & Michael F. Weaver

To cite this article: Jin H. Yoon, Scott D. Lane & Michael F. Weaver (2015) Analgesics and Nicotine: More Than Blowing Smoke, Journal of Pain & Palliative Care Pharmacotherapy, 29:3, 281-289, DOI: 10.3109/15360288.2015.1063559 To link to this article: http://dx.doi.org/10.3109/15360288.2015.1063559

Published online: 16 Sep 2015.

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Download by: [University of Colorado - Health Science Library] Date: 21 September 2017, At: 08:49 Journal of Pain & Palliative Care Pharmacotherapy. 2015;29:281–289. Copyright © Taylor & Francis Group, LLC ISSN: 1536-0288 print / 1536-0539 online DOI: 10.3109/15360288.2015.1063559

SYMPTOM MANAGEMENT AND SUBSTANCE MISUSE Opioid Analgesics and Nicotine: More Than Blowing Smoke

Jin H. Yoon, Scott D. Lane, and Michael F. Weaver

ABSTRACT Practitioners are highly likely to encounter patients with concurrent use of nicotine products and opioid anal- gesics. Smokers present with more severe and extended chronic pain outcomes and have a higher frequency of prescription opioid use. Current is a strong predictor of risk for nonmedical use of prescription . Opioid and nicotinic- systems interact in important ways to modulate opioid and nicotine effects: release induced by nicotine is dependent on facilitation by the opioid system, and the nicotinic- system modulates self-administration of several classes of abused —including opioids. Nicotine can serve as a prime for the use of other drugs, which in the case of the opioid system may be bidirectional. Opioids and compounds in tobacco, including nicotine, are metabolized by the enzyme system, but the of opioids and tobacco products can be complicated. Accordingly, interactions are possible but not always clear. Because of these issues, asking about nicotine use in patients taking opioids for pain is recommended. When assessing patient tobacco use, practitioners should also obtain information on products other than , such as , pipes, , and electronic nicotine delivery systems (ENDS, or e-cigarettes). There are multiple forms of behavioral therapy and pharmacotherapy available to assist patients with , and opioid maintenance and pain clinics represent underutilized opportunities for nicotine intervention programs. KEYWORDS chronic pain, drug interactions, nicotine, opioids

CONCURRENT USE OF NICOTINE AND lihood of overlap among these groups, especially in OPIOIDS clinical settings. Recent epidemiological studies have demonstrated that smokers are more likely to be on , Practitioners are highly likely to encounter patients LTOT.3 4 In fact, smokers may need higher opioid who use both nicotine products and opioid analgesics. doses, as shown in several recent clinical A significant proportion of the US population smokes studies.5–7 or uses other nicotine products, such as chewing to- Smokers may have an increased risk of developing bacco or electronic cigarettes, around 20% of adults.1 chronic pain.8–10 Smokers with chronic pain com- At least 3% of adults receive long-term opioid ther- plain of pain of greater severity and at more body 2 11 Downloaded by [University of Colorado - Health Science Library] at 08:49 21 September 2017 apy (LTOT) for chronic pain. There is a high like- sites. Of particular interest is the often-reported re- lationship between smoking and back pain.10 In rel- Jin H. Yoon, PhD, is Assistant Professor of Psychiatry and Behavioral atively recent prospective cohort studies, some have Sciences, Center for Neurobehavioral Research on , University noted a -dependent relationship between ado- of Texas Health Sciences Center at Houston, Houston, Texas, USA. Scott lescent smoking and the development of back pain D. Lane, PhD, is Professor and Vice-Chair for Research in Psychiatry and 12 13 Behavioral Sciences, Center for Neurobehavioral Research on Addictions, among adolescents and twins. One study includ- University of Texas Health Sciences Center at Houston, Houston, Texas, ing over 50,000 adolescents observed daily smok- USA. Michael F. Weaver, MD, FASAM, is Professor of Psychiatry and Be- ing to be one of the strongest risk factors for low havioral Sciences and Medical Director, Center for Neurobehavioral Re- search on Addictions, University of Texas Health Sciences Center at Hous- back pain hospitalization, and this association per- ton, Houston, Texas, USA. sisted into adulthood.14 Overall, smokers experience Address correspondence to: Michael F. Weaver, MD, FASAM, The Univer- a greater impact of pain on occupational and so- sity of Texas Health Science Center at Houston, 1941 East Road, BBSB 1222, 15,16 Houston, TX 77054, USA (E-mail: [email protected]). cial functioning than nonsmokers. Smokers also

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tend to have worse chronic pain outcomes with more the most common class of misused prescription disability.17,18 drugs. misuse was associated with High rates of nicotine use are well documented and illicit drug use, but was not in the drug-abusing population. A review of nico- associated with nicotine smoking. tine smoking rates among drug abusers summariz- The substantial evidence linking nicotine smok- ing the literature between 1987 and 2009 reported ing and opiate use argues for a neurobiological in- aggregated (cross-drug class) smoking rates rang- teraction between the neurotransmitter systems that ing between 65% and 75% annually.19 Notably, the underlie the actions of opiates (opioid system) and highest odds ratio (OR) for any drug class was nicotine (nicotinic-cholinergic system). Indeed, as re- among individuals in maintenance pro- viewed in the section, these two transmitter sys- grams (OR = 2.25). Other reviews of methadone tems interact in important ways to modulate opi- maintenance patient populations estimate nicotine ate and nicotine effects on drug reward, drug toler- smoking rates between 74% and 94%.20 A study of ance, , and nociception. Knowledge 305 users on agonist (i.e., substitution) ther- of these interactions has led clinicians to utilize opi- apy with methadone or found that oid antagonists to promote cessation from nicotine 97% were smokers, using an average of ap- smoking. However, reviews and meta-analyses indi- proximately 20 cigarettes per day.21 In addition to cate that the use of opioid antagonists (particularly the unequivocal data in methadone-maintained in- ) provide no benefit over , either as dividuals, the majority of heroin users are nicotine a stand-alone pharmacotherapy or as an adjunct to smokers (heroin is a ), and nicotine nicotine replacement.26 smoking may actually extend the duration of heroin Nicotine produces antinociception in preclincial .22 models,27,28 and cigarette smoking rates are elevated Tobacco-related mortality and morbidity is in patients with chronic pain.29 Accordingly, nicotine accordingly high in prescription opioid users. has been examined as an analgesic for postoperative Methadone and other opioid treatment programs pain; the most common modalities have been nico- represent opportunities for the development of tine patch and nasal spray. However, a recent review smoking intervention programs in the opiate-using and meta-analysis found that the use of nicotine as population.23 A recent review noted that current an analgesic increased postoperative and did smoking intervention efforts in methadone main- not reduce pain in a statistically significant fashion.30 tenance programs generally precipitate short-term However, this review did find that postoperative use reductions in smoking but have been largely unsuc- of nicotine did significantly reduce the need for opi- cessful in promoting sustained abstinence.24 One oids 24 hours post operation. Perhaps counterintu- review cites long-term abstinence rates <10%.20 itively, nicotine smoking increases risk for chronic Although nicotine use rates in methadone- pain symptoms.10,25 In summary, nicotine has not maintained individuals are well documented, there been demonstrated as a clinically effective analgesic is a troubling scarcity of population-level data in humans. regarding nicotine use among both licit and illicit users of prescription opiates. Although it may be reasonable to conclude—based on smoking rates in INTERACTIONS BETWEEN methadone users and in the general drug-abusing ENDOGENOUS OPIOID AND population—that nicotine use rates are also much CHOLINERGIC SYSTEMS higher in prescription opiate users than in the general population, public health/epidemiological data from The endogenous opioid system is a diffuse and com-

Downloaded by [University of Colorado - Health Science Library] at 08:49 21 September 2017 US samples are currently needed. One population- plex component of the central nervous system (CNS). based study using health surveys in Norway found It interacts with many of the major neurotransmitter that frequency of prescription opiate use was greater systems and plays a direct or modulating role in facili- in both men and women with a .25 tating the action of many drugs of abuse.31 In addition Importantly, this study found that odds ratios for to abused opiates, there is both preclinical and clin- prescription opioid use increased as a function of ical evidence to suggest that the endogenous opioid severity of nicotine use (dependent daily smokers: system interacts with drugs that act on dopaminer- OR = 3.1), suggesting a dose-response relationship gic, , and (most relevant to the present between frequency of nicotine use and amount report) nicotine-acetylcholine .28,32,33 of prescription opiate use.25 A study based on a The endogenous opioid system involves at least sample from Alberta, Canada, focused on past-year three major peptide classes that facilitate neuro- prescription drug misuse found that opiates were chemical transmission: beta-endorphins; met-, and

Journal of Pain & Palliative Care Pharmacotherapy Symptom Management and Substance Misuse 283

leu-enkephalins; and dynorphins; and three classes In vitro studies demonstrate that morphine binds of G-protein-coupled opioid receptors: mu, delta, to and functionally interacts with α4β2 receptors in and kappa. A fourth peptide and the correspond- the CNS, providing one mechanism through which ing , nociceptin/orphanin FQ, have more re- morphine exerts its reinforcing/euphoric effects.35 cently been identified, but are less well characterized Like morphine, prescription opiates such as oxy- than the extensively studied mu, delta, and kappa codone and bind to the mu receptor, systems27,28. The three receptor peptide classes ap- but also exert action on delta receptors.36 They are pear to have unique properties and different affinities thus likely to interact with the nicotinic-acetylcholine for the three major receptor units. Of relevance to this system in a fashion similar to morphine. review, the delta receptor is known to regulate analge- Notably, increasing evidence implicates the sia and ; the kappa receptor fa- nicotinic-acetylcholine system in modulating the cilitates and dysphoric effects and modu- intake (including self-administration) of several lates stress reactions; and the mu receptor (for which classes of abused drugs, including (clearly) nicotine, morphine/heroin has the greatest affinity) facilitates and also opioids, , , and marijuana. and physical dependence.34 This observation may be linked to the established Similar to the opiate system, the nicotinic- finding that nicotine can serve as a prime for the use cholinergic system interacts with and modulates of other drugs.37 In the case of the opioid system, the action of several other neurotransmitter sys- this priming effect may be bidirectional; a postulate tems, including dopamine, norepinephrine, gluta- supported both by the biochemical interactions of mate, and most notably the opioid system.28,35 The the nicotinic-acetylcholine and opioid systems, and nicotinic-acetylcholine system has two major recep- the alarmingly high rates of smoking among opiate tor classes: alpha (α) and beta (β), with a range users. of identified subunitsα ( 2–α10 and β2–β4), which are -gated ion channels. The most abundant, widely distributed, and arguably most well-studied CHRONIC PAIN, NICOTINE USE, AND subtypes with regard to nicotine and other drugs OPIOID ANALGESICS of abuse are the α7 and the α4β2 complex. The α4β2 complex is believed to mediate nicotine rein- Pain can be the result of injury or disease such as forcement by activating dopamine transmission, as in the case of postoperative pain or cancer-related well as stimulating the release of the opioid pep- pain. Pain can also be the disease itself, such as in the tides (i.e., beta-endorphins, enkephalins, and dynor- case of neuropathic pain. Neuropathic pain refers to phins) in the and nucleus ac- pain resulting from damaged nerves, contrasting with cumbens, particularly via action at the mu opioid nociceptive pain caused by damage to body tissue. receptor.32 Thus, CNS dopamine release induced by Chronic pain is widely experienced by the general nicotine administration is dependent on facilitation population, causing significant loss of quality of life by the opioid system. In particular, the following and morbidity38,39 and has substantial public health relationships have been identified: (i) the endoge- costs. Approximately 1 out of every 3 (100 million) nous opioid enkephalins and beta-endorphins act Americans experiences chronic pain, but as described on mu receptors in facilitating the reinforcing ef- earlier, only 3% of adults receive LTOT for chronic fects of nicotine; (ii) the aversive effects of nicotine pain.2 (e.g., nausea, negative emotional states) appear to be The first step in pain relief typically in- facilitated by dynorphins and delta and kappa recep- volves administration of nonprescription, oral med- tor systems; and (iii) the enkephalin peptides and ications such as aspirin, acetaminophen, or nons-

Downloaded by [University of Colorado - Health Science Library] at 08:49 21 September 2017 mu receptors largely facilitate the somatic compo- teroidal anti-inflammatory drugs (NSAIDs). If these nents of .33 Further, it is sug- are not effective in controlling pain, opi- gested that the α7 nicotinic subunit interacts with the oids may be administered either in conjunction with endogenous opioid system to facilitate physical de- the above medications or as a replacement. Rela- pendence, whereas the α4β2 nicotinic subunit com- tively weaker opiates are administered orally. Some plex interacts with mu opioid receptors in the ventral opioids can be administered orally, but others are tegmental area, , and extended also administered transdermally via patches (e.g., fen- amygdala (key components of the well-established tanyl), through , or through injections mesocorticolimbic reinforcement pathway) to modu- or with an external infusion system. The existence late nicotine reinforcement and facilitate psychologi- of endogenous opioids (endorphins, enkephalins, and cal dependence.27 dynorphins) was discovered in 1975. The majority of

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opioids are , with common examples includ- phone, tapentadol, ) are less likely to ing morphine, hydromorphone, , methadone, have drug-drug interactions.43 and . Among opioid analgesics, there also The distribution of enzymes can be varied across exist partial agonists such as buprenorphine as well as individuals, with polymorphisms that can drug mixed agonists, including butorphanol, nalbuphine, metabolism. For example, CYP3A activity can vary and . The latter should be used with 5-fold, but this variability can increase to 400-fold caution, as analgesic effects plateau with increasing as a result of drug-drug interactions.44 These genetic dose and may actually reverse the effects of agonist variations are categorized into four groups: poor me- opioids.40 tabolizers, intermediate metabolizers, extensive me- There has been increasing awareness and interest tabolizers, and ultrarapid metabolizers.48 For exam- in the relationship across opioid use, cigarette smok- ple, CYP2D6 metabolizes to morphine and ing, and chronic pain.10 A commonly observed trend to O-desmethyltramadol. Individuals with is higher rates of cigarette smoking among individuals the ultrarapid metabolizing phenotype are susceptible using a variety of drugs.41,42 This effect has not been to from the metabolized forms.49 Conversely, as widely reported for individuals receiving LTOT individuals who are slow metabolizers of CYP2B6 are for pain, but this may reflect the relatively recent in- also susceptible to methadone toxicity due to slower crease in individuals receiving LTOT rather than the methadone metabolism.50 CYP3A4 and CYP2D6 absence of a specific relationship between opioids re- are the most relevant P450 enzymes in relation to ceived for chronic pain and smoking. Nicotine itself opioid metabolism. The majority of CYP3A4 poly- is known to have analgesic effects, but generally in- morphisms result in decreased enzyme function. The duces nausea among individuals who do not receive proportion of patients without a genetic polymor- nicotine chronically. phism is relatively low, except for specific poly- morphisms in Hispanics and Indo-Pakistanis. In re- gards to CYP2D6, the wild-type consists of extensive metabolizers.51 The majority of polymorphisms re- DRUG INTERACTIONS BETWEEN sults in decreases or absent enzyme activity, although OPIOIDS AND NICOTINE one polymorphism has been identified to increase en- zyme activity. African Americans and Asians are at Drugs are metabolized by chemical reactions that fall the greatest risk for being poor metabolizers.52 An ex- into two categories. Phase I reactions include hydrol- haustive review on the topic is available in a series of ysis and oxidation, whereas Phase II reactions involve articles by Zhou and colleagues.53–55 making substances more hydrophilic.43 For opioids, Cigarette smoking also affects both Phase I and the most important Phase II reaction is glucuronida- II reactions. In regards to Phase I reactions, smok- tion, which is catalyzed by uridine diphosphate glu- ing primarily induces CYP1A1 and CYP1A2 and curonosyltransferase (UGT). In regards to Phase I re- less consistently CYP2E1.56–58 Cigarette smoking actions, approximately half of all medications, includ- enhances CYP1A2 via polycyclic aromatic hydrocar- ing many opioids, are metabolized by the cytochrome bons binding to aryl hydrocarbon receptors, which P450 enzyme system.44–46 The cytochrome P450 consequently transcriptionally activates the CYP1A2 (CYP450) enzyme system is involved in the pharma- gene.57 As noted above, individuals on methadone cokinetics of multiple drugs, including nicotine and maintenance engage in high rates of cigarette smok- opiates. The CYP450 system comprises a number of ing in a dose-dependent manner. Methadone is enzymes. Over 30 enzymes have been identified as primarily metabolized by CYP3A4, but also by part of the CYP450 system, with more likely to be dis- CYP1A2 to a lesser degree. In a recent case study,

Downloaded by [University of Colorado - Health Science Library] at 08:49 21 September 2017 covered, but 90% of human drug oxidation can be at- methadone toxicity was observed in an individual on tribute primarily to six enzymes (i.e., CYP1A2, 2C9, a program who had stopped 2C19, 2D6, 2E1, and 3A4/5).47 Opioids that undergo smoking.59 CYP1A2 induces a number of drugs, in- Phase I metabolism are catalyzed predominately by cluding duloxetine, a serotonin-norepinephrine re- CYP3A4 and CYP2D6 (e.g., codeine, hydrocodone, uptake inhibitor, which can be prescribed for neu- oxycodone, methadone, tramadol, fentanyl, hydro- ropathic pain. The effects of smoking on CYP2E1 morphone) and are therefore prone to possible drug- appears to be relatively moderate and not present drug interactions.43,46 In the case of the CYP450 sys- in all individuals.56 However, CYP2E1 is of in- tem, drug-drug interactions can result when one drug terest, as it is involved in the metabolism of ac- induces or inhibits one of the CYP450 enzymes. In etaminophen as well as ethanol and may activate contrast, opioids that are primarily metabolized by smoking-related carcinogens.60,61 Therefore, induc- UGT via Phase II reactions (e.g., morphine, oxymor- tion of CYP2E1 may lead to acetaminophen hepa-

Journal of Pain & Palliative Care Pharmacotherapy Symptom Management and Substance Misuse 285

totoxicity and explain individual variation in the de- patient and practitioner. An affirmative answer can velopment of smoking-related cancer. Interestingly, be followed up with some additional questions about smoking appears to inhibit CYP2A6, which is pri- quantity and frequency of tobacco product use in a marily responsible for the metabolism of nicotine.58,62 matter-of-fact manner, which helps set the stage for In regards to Phase II reactions, polycyclic aryl later questions about substance use with a nonthreat- hydrocarbons in cigarette smoking induces UGT- ening approach. Obtaining information about smok- related metabolism,63,64 including codeine.65 Al- ing can be very important as a predictor for potential though it has been consistently observed that smok- patient outcomes. ers have increased requirements for opioids postoper- Smoking has been associated with nonmedical use atively, the metabolism of various opiates can be com- of prescription opioids. The strongest predictor of plicated, so the relationship between smoking and higher risk for nonmedical use of prescription opi- UGT is not clear.66 oids is a history of , especially poly- Other issues should be considered when faced with substance abuse, although a significant single sub- cigarette smoking. In vitro studies have observed car- stance identified in various research studies is current bon monoxide (CO) to inhibit the CYP450 system.56 .70 However, history alone is usu- For example, CO inhibited CYP2D6 enzymes in ally insufficient to predict risk accurately and should human microsomes,67 but this effect has not be combined with collateral information from sig- been observed clinically in humans.62 In addition to nificant others and previous health care providers.71 CO, the presence of trace amounts of heavy metals A likely reason for the association between higher such as cadmium, nickel, chromium, lead, and ar- risk for opioid misuse and nicotine use is because senic may potentially have effects on the CYP450 nicotine is a known addictive substance, so tobacco system in humans.68 Additionally, psychodynamic ef- users have already demonstrated establishment of fects of smoking decreasing the analgesic efficacy of at least one . Nicotine is a potent gate- the opioids propoxyphene (discontinued) and penta- way drug for diverse illegal drugs,72 especially among zocine have been noted, although the mechanism is adolescents.73 With the revelation of use of one ad- unknown.58 dictive substance, patients are at higher risk for man- ifestation of addiction to other substances, including opioid analgesics, due to the presence of shared risk GUIDELINES FOR PRESCRIBERS factors. Cigarettes are the most prevalent form of tobacco It is good for practitioners who prescribe opioid anal- consumption in the United States, but not the only gesics to be aware of the connections between opioid popular nicotine delivery method. When asking about use and nicotine use. This can help improve prescrib- nicotine or tobacco products, it is often useful to in- ing practices in terms of patient safety and treatment clude an open-ended question, such as, “What types outcomes. of tobacco or nicotine products have you used?” This In terms of risk assessment for patients for whom provides an opportunity to obtain information on to- the practitioner is considering a therapeutic trial of bacco products other than cigarettes, such as cigars, opioid analgesics, asking about nicotine use can be , pipes, pipes, smokeless tobacco valuable. Since there is no definitive test to predict (, ), and electronic nicotine delivery systems which patients will do well with a therapeutic trial (ENDS, or e-cigarettes).74 It is helpful for clinicians of opioids for chronic pain, it makes sense to take a to ask about specific products by name, since pa- “universal precautions” approach to all patients with tients may not consider ENDS to be a “tobacco prod- chronic pain.69 This reduces stigma, improves pa- uct” or may not realize that a hookah pipe contains

Downloaded by [University of Colorado - Health Science Library] at 08:49 21 September 2017 tient care, and reduces risks by adopting a minimum tobacco.75 Asking specifically about a variety of nico- level of care applicable to all patients presenting with tine products allows a prescriber to more accurately chronic pain. Universal precautions include asking determine the impact of nicotine consumed on the patients about personal and family history of sub- patient’s chronic pain and use of opioid analgesics. stance use. A less threatening way to begin gather- Although ENDS may have the potential for less ing information about substance use from patients physical harm compared with tobacco, due to the is to start by asking about use of nicotine products. fact that they do not deliver monoxide and Because tobacco products are legal and relatively so- some carcinogens,76,77 they do deliver nicotine. As cially acceptable, asking patients about smoking is with other drugs of abuse, including opioids, users generally nonthreatening and allows the patient to may escalate the dose due to physical tolerance. Users give a yes-or-no answer to a straightforward ques- may also tamper with the ENDS to provide larger tion. This is simple and often routine for both the doses of nicotine, or make changes to the liquid that is

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used in these devices (“e-liquid”). One of the ways in pathic pain88 as well as smoking cessation and depres- which users tamper with ENDS is by “dripping.”78 To sion, all of which may be present concurrently among engage in “dripping,” the user applies the e-liquid di- patients with chronic nonmalignant pain. Awareness rectly from the bottle onto the heating element of the of nicotine use and patient level of interest in quitting ENDS and then inhales the vapor produced. Drip- can help with selection of therapeutic options, espe- ping has gained popularity through dissemination via cially those that may be effective for multiple condi- the Internet, and specialized “drip tips” are avail- tions. able for purchase.74 This process may provide a larger dose of nicotine when a nicotine-containing solution is used, but also allows for higher exposure to by- RESEARCH DIRECTIONS products of heating the other ingredients of the liquid, such as .79 Another method of tamper- Currently, the extant literature suggests that impor- ing with ENDS is by mixing different e-liquids with tant and clinically significant interactions exist be- higher concentrations of nicotine. Variable-voltage tween opioids, cigarette smoking, and pain. However, ENDS are available, and higher voltage appears to multiple areas of this relationship clearly need fur- increase the nicotine yield of the vapor.80 Asking pa- ther investigation. First and foremost, a clearer pic- tients about unorthodox use of ENDS is helpful to ture between the relationship between LTOT use and determine the risk of harm. Intentional misuse of cigarette smoking is needed. High rates of comorbid- ENDS puts the patient at higher risk for intentional ity would not be surprising given the documented re- misuse of other substances, including prescribed opi- lationship among methadone-maintained individuals oid analgesics. and other populations such as those with cocaine use While asking about nicotine product use, practi- disorders41,42,89–94 and problem drinking.95–99 Once tioners can take advantage of the opportunity to ad- this information is gathered, researchers can begin to dress smoking cessation with the patient. Patients better understand how smoking affects the analgesic who use tobacco products perceive the advice from a effects of opioids. Although the current review high- health care professional to quit as a strong motivator lights some of these findings, there is a lack of knowl- for a cessation attempt.81–83 Providing appropriate, edge regarding the effects of smoking on the analgesic accurate information about risks of tobacco products, effects on the vast majority of commonly prescribed and encouraging healthy choices, can help patients to opioids. make the best informed decision about changing be- Another important area of future research is how havior with respect to use of nicotine.74 The respon- ENDS use may affect opioid analgesia. Growing ev- sibility of the practitioner is to motivate the patient idence supports that ENDS can transmit a num- to seek recovery from nicotine use instead of blaming ber of biologically relevant substances beyond just the patient for being unmotivated to change.84 Brief nicotine.100,101 This area of study will likely face sub- counseling provided by a clinician in a health care stantial challenges given the general lack of regulation setting significantly increases nicotine quit rates ver- regarding ENDS devices and the rapidly growing va- sus no counseling.85 There are multiple forms of be- riety of ENDS products and their uses.75 havioral therapy available, including smoking cessa- Finally, a number of clinically important areas tion group counseling or individual therapy based on also exist that would benefit from further explo- cognitive-behavioral principles. Randomized control ration. For example, there has been growing aware- trials demonstrate that nicotine replacement therapy, ness that smoking cessation prior to surgery can , and all increase the long-term improve a number of important surgical outcomes success of quit attempts for tobacco smoking.86 Clin- such as wound healing.102 However, little is known

Downloaded by [University of Colorado - Health Science Library] at 08:49 21 September 2017 icians can also refer patients to the national toll-free how this might affect the efficacy and appropriate telephone quitline number, 800-QUIT-NOW (800- dose of opioids used during and following surgery. 784-8669), or to a Web site (www.smokefree.gov) Given the case report on methadone toxicity follow- maintained by the US Department of Health and Hu- ing smoking cessation reported above and general man Services to provide information to download to lack of knowledge regarding opioid and smoking in- make cessation easier. teractions, there may be important clinical risks that Patients with chronic pain who express an interest have yet to be discovered. Also, an interesting rela- in nicotine cessation may benefit from medications to tionship between chronic smoking and higher suscep- assist with this. Bupropion is a prescribed polycyclic tibility to developing back pain has been repeatedly antidepressant that is also started prior to tobacco reported.10 However, the exact mechanism of this re- cessation and continued for 3–6 months of therapy.87 lationship is still unknown. For example, do smokers Bupropion has been shown to be effective for neuro- simply engage in unhealthy behaviors (poor posture,

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other unhealthy behaviors) that affect the develop- [15] Weingarten TN, Podduturu VR, Hooten WM, Thompson JM, ment of back pain, or does cigarette smoking some- Luedtke CA, Oh TH. Impact of tobacco use in patients pre- how inhibit the healing or even directly damage the senting to a multidisciplinary outpatient treatment program for fibromyalgia. ClinJPain.2009;25:39–43. spine and related muscle groups? [16] Weingarten TN, Sprung J, Flores A, Baena AM, Schroeder Overall, evidence strongly suggests that cigarette DR, Warner DO. Opioid requirements after laparoscopic smoking and opioid use are intimately intertwined bariatric surgery. Obes Surg. 2011;21:1407–1412. and that dual use may have clinically significant ef- [17] Hagen KB, Tambs K, Bjerkedal T. A prospective cohort study fects on opioid analgesia. However, it is also clear that of risk factors for disability retirement because of back pain in the general working population. Spine. 2002;27:1790–1796. important details of this relationship have not been di- [18] Lincoln AE, Smith GS, Amoroso PJ, Bell NS. The natural his- rectly explored, and the field would benefit from di- tory and risk factors of musculoskeletal conditions resulting in rect and targeted investigations. disability among US Army personnel. Wo r k . 2002;18:99–113. [19] Guydish J, Passalacqua E, Tajima B, Chan M, Chun J, Declaration of interest: The authors report no con- Bostrom A. Smoking prevalence in addiction treatment: a re- flicts of interest. The authors alone are responsible for view. Nicotine Tob Res. 2011;13:401–411. [20] Zirakzadeh A, Shuman C, Stauter E, Hays JT, Ebbert JO. the content and writing of the paper. Cigarette smoking in methadone maintained patients: an up- to-date review. Curr Drug Abuse Rev. 2013;6:77–84. [21] Pajusco B, Chiamulera C, Quaglio G, et al. Tobacco addic- REFERENCES tion and smoking status in heroin addicts under methadone vs. buprenorphine therapy. Int J Environ Res Public Health. 2012;9:932–942. [1] Centers for Disease Control and Prevention. Current cigarette [22] Li L, Liu Y, Zhang Y, Beveridge TJ, Zhou W. Temporal smoking among adults—United States, 2005–2012. MMWR changes of smoking status and motivation among Chinese Morb Mort Wkly Rep. 2014;63:29–34. heroin-dependent, methadone-maintained smokers. Addict Be- [2] Boudreau D, Von Korff M, Rutter CM, et al. Trends in long- hav. 2010;35:861–865. term opioid therapy for chronic non-cancer pain. Pharmacoepi- [23] Richter KP, Ahluwalia JS. A case for addressing cigarette use demiol Drug Saf. 2009;18:1166–1175. in methadone and other opioid treatment programs. J Addict [3] Rogal SS, Winger D, Bielefeldt K, Szigethy E. Pain and opioid Dis. 2000;19:35–52. use in chronic liver disease. Digest Dis Sci. 2013;58:2976–2985. [24] Okoli CT, Khara M, Procyshyn RM, Johnson JL, Barr AM, [4] Dobscha SK, Morasco BJ, Duckart JP, Macey T, Deyo Greaves L. Smoking cessation interventions among individuals RA. Correlates of prescription opioid initiation and long- in methadone maintenance: a brief review. J Subst Abuse Treat. term opioid use in veterans with persistent pain. ClinJPain. 2010;38:191–199. 2013;29:102–108. [25] Skurtveit S, Furu K, Selmer R, Handal M, Tverdal A. Nico- [5] Qiu YM, Liu YT, Li ST. Tramadol requirements may need tine dependence predicts repeated use of prescribed opioids. to be increased for the perioperative management of pain in Prospective population-based cohort study. Ann Epidemiol. smokers. Med Hypotheses. 2011;77:1071–1073. 2010;20:890–897. [6] Steinmiller CL, Diederichs C, Roehrs TA, Hyde-Nolan M, [26] David SP, Chu IM, Lancaster T, Stead LF, Evins AE, Roth T, Greenwald MK. Postsurgical patient-controlled opi- Prochaska JJ. Systematic review and meta-analysis of oid self-administration is greater in hospitalized abstinent opioid antagonists for smoking cessation. BMJ Open. smokers than nonsmokers. J Opioid Manage. 2012;8:227–235. 2014;4:e004393. [7] Ackerman WE 3rd. The effect of cigarette smoking on hy- [27] Kishioka S, Kiguchi N, Kobayashi Y, Saika F. Nicotine ef- drocodone efficacy in chronic pain patients. J Ark Med Soc. fects and the endogenous opioid system. J Pharmacol Sci. 2012;109:90–93. 2014;125:117–124. [8] Scott SC, Goldberg MS, Mayo NE, Stock SR, Poitras B. The [28] Xue Y, Domino EF. Tobacco/nicotine and endogenous association between cigarette smoking and back pain in adults. opioids. Prog Neuropsychopharmacol Biol Psychiatry. Spine. 1999;24:1090–1098. 2008;32:1131–1138. [9] Palmer KT, Syddall H, Cooper C, Coggon D. Smoking and [29] Ekholm O, Gronbaek M, Peuckmann V, Sjogren P. Alcohol musculoskeletal disorders: findings from a British national sur- and smoking behavior in chronic pain patients: the role of opi- vey. Ann Rheum Dis. 2003;62:33–36. oids. Eur J Pain. 2009;13:606–612. [10] Shi Y, Weingarten TN, Mantilla CB, Hooten WM, Warner [30] Mishriky BM, Habib AS. Nicotine for postoperative anal-

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