Opioids are currently the most widely prescribed class of medications (mu-opioid receptor agonists; Center for Disease Control and Prevention, 2015), and opioid misuse (defined as using a substance other than how it is indicated or prescribed; Butler et al., 2007) constitutes a significant public health problem in the United States (US; Brady et al., 2016). Despite efforts to curb this increasing epidemic, opioid-related overdoses and deaths are at an all-time high (Center for Disease Control and Prevention, 2016; Nelson and Perrone, 2012). Importantly, opioids are often prescribed for the treatment of chronic pain (Daubresse et al., 2013; Dowell et al., 2016), and despite evidence suggesting that opioids are effective at managing chronic pain in the short term (Chou et al., 2015), opioid use in the context of pain management is associated with increased risk of morbidity and mortality. Specifically, opioid use in the context of chronic pain has been associated with risk of opioid misuse, greater anxiety and depression, increased pain sensitivity, and comorbidity with other substance use disorders (Chou et al., 2009, 2015; Chu et al., 2006; Dowell et al., 2016; Edlund et al., 2007). Empirical evidence further suggests a bi-directional relationship, such that these comorbidities are also associated with increased risk for opioid misuse (Brooner et al., 1997; Wilsey et al., 2008). Collectively, this research highlights the public health importance of examining these comorbidities.
Cannabis is another substance that is often used to manage chronic pain (Manchikanti et al., 2006), and more people have reported access to, and use of cannabis following the legalization for medical purposes in many states (Cerdá et al., 2012). Cannabis plant-derived products include the well know delta-9-THC (cannabinoid receptor-1 agonist), as well as other compounds like cannabidiol (McCarberg and Barkin, 2007). Although preliminary evidence from randomized controlled trials provides evidence for the efficacy of cannabis for pain management (Deshpande et al., 2015; Hill, 2015; Jensen et al., 2015), results remain mixed regarding the long-term consequences of cannabis use, particularly in the context of chronic pain (Deshpande et al., 2015; Hill et al., 2017). For example, in the general population, cannabis use is often associated with elevated mental health problems (Buckner et al., 2010; Grant et al., 2004; Jané-Llopis et al., 2006), increased healthcare costs (Pacula et al., 2008), and changes in pain tolerance (increased, but not better than a benzodiazepine; Raft et al., 1977). However, more recent research suggests there may be some utility in using cannabis to manage pain among individuals with chronic pain conditions (Bar-Lev Schleider et al., 2018).
In general, the co-use of substances, defined as using more than once substance at a time, is associated with greater adverse effects compared to single substance use (Kandel et al., 2001; Weinberger et al., 2010). For example, past work has shown that the risk of using more than one substance (eg, alcohol and tobacco) is greater than the independent risk of using either substance alone (Taylor and Rehm, 2006). Some research suggests that substances may be used together (cocaine and heroin) to induce novel subjective effects that are not experienced during the exclusive use of a single substance (Leri et al., 2003). Research shows that polysubstance use behavior is prominent among youth (Moss et al., 2014), and polysubstance use is generally associated with elevated mental health problems, as well as more severe substance use problems (Kandel et al., 2001; Martinotti et al., 2009). Yet little attention has been paid to the impact of opioid and cannabis co-use, despite increased use of both substances among individuals with chronic pain.
The use of both opioids and cannabis concurrently in response to pain may be possible because of the legalization of cannabis for medical purposes in many states (Bachhuber et al., 2014). This co-use may represent a vulnerability associated with increased risk of morbidity and mortality among individuals with chronic pain. People who use medical cannabis are more likely to report nonmedical use of prescription medications (including prescription pain medications) compared to those who do not use medical cannabis (Caputi and Humphreys, 2018). Additionally, cannabis use has been associated with current opioid misuse, as well as an increased likelihood of future opioid misuse (Fiellin et al., 2013).
Given the dearth of work examining these relations among individuals with chronic pain, there is a critical public health need to better understand the impact of cannabis use in the context of opioid use for chronic pain. Additionally, no research has directly compared individuals who only use opioids to those who use both opioids and cannabis. This limitation is unfortunate, because without this comparison, it is not possible to isolate and quantify the impact of cannabis use in the context of opioid use for chronic pain. Therefore, the current study sought to compare people who use solely opioids to people who co-use opioids and cannabis, among adults with chronic pain. It was hypothesized that, compared to those using opioids without cannabis, those that co-use opioid and cannabis would report elevated opioid misuse, pain experience, anxiety, depression, and other substance use problems, including tobacco, alcohol, cocaine, and sedatives.
Participants were asked about their sex, race, age, educational level, annual income, and marital status.
Alcohol, Smoking, and Substance Involvement Screening Test
The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) is an 8-item questionnaire designed to asses risk a wide range of substance misuse, including tobacco, alcohol, cannabis, cocaine, among others (Humeniuk et al., 2008). Past work has documented strong psychometric properties for the ASSIST (citation). Participants rate their uses (eg, frequency, urge, problems/consequences) for each substance they use on a 5-point Likert scale. Total scores for each substance is calculated as well as a risk level, where higher scores indicated greater substance involvement, including frequency of use and problems associated with use. In the current study, the question “Have you used Cannabis in the past 3 months,” was used to classify participants as using cannabis or not. Total substance involvement scores for tobacco (α = 0.85), alcohol (α = 0.90), cocaine (α = 0.94), and sedatives (α = 0.88) were calculated by summing all items associated with each substance, and each total score and showed strong internal consistency.
Patient Health Questionnaire-4
The patient Health Questionnaire-4 (PHQ-4) is a 4-item self-report measure, rated on a 5-point Likert scale from 0 (not at all) to 4 (nearly every day). The PHQ-4 is comprised of the PHQ-2 for depression (eg, item) and the GAD-2 (eg, item) for anxiety (Kroenke et al., 2003; Kroenke et al., 2007; Löwe et al., 2005) and the total score and subscales (anxiety and depression) have been previously validated (Löwe et al., 2010). PHQ-4 values that are greater than 5 are considered moderate to severe depression and/or anxiety (Löwe et al., 2010). The total score for depression consists of the sum of the 2 depression items, and the total score for anxiety consists of the sum of the 2 anxiety items. The PHQ-4 anxiety (α = 0.87) and PHQ-4 depression (α = 0.89) subscales were used and showed strong internal consistency.
Current Opioid Misuse Measure
The Current Opioid Misuse Measure (COMM) derives a total score from 17 items (eg, item) to identify individuals who are exhibiting behaviors of opioid misuse (Butler et al., 2007). Each item is rated on a 5-point scale from 0 (never) to 4 (very often) to create a sum total score (α = 0.97) with excellent internal consistency. Test-retest reliability has been established and construct validity demonstrated with positive correlations for urine toxicology results among individuals with chronic pain (Butler et al., 2007; Wasan et al., 2007).
Severity of Dependence Scale
Severity of Dependence Scale (SDS) is a 5-item (eg, item) measure severity of dependence to opioids (Gossop et al., 1995). Responses are rated on a 4-point scale from 0 (Never) to 3(Always), and all items are summed for a total score (Iraurgi Castillo et al., 2010) and SDS total score was used (α = 0.86) showing strong internal consistency.
Graded Chronic Pain Scale
The Graded Chronic Pain Scale (GCPS) assesses pain intensity and pain disability on an 8-item self-report scale (Von Korff et al., 1992). Past work has demonstrated strong psychometric properties of the GCPS among individuals with chronic pain (Von Korff et al., 1992). Items pertaining to pain severity are rated on 10-point scale from 0 (No pain) to 10 (Pain as bad as could be) and summed, and items pertaining to pain disability are rated on a 10-point scale from 0 (No interference) to 10 (Unable to carry on activities) and summed to create 2 total scores. Higher scores are indicative of more severe and disabling pain. The GCPS pain intensity (α = 0.84) and pain disability (α = 0.91) scales were examined in this study and showed strong internal consistency.
All procedures were carried out by means of online data entry. Participants were recruited nationally through Qualtrics, an online survey management system during the summer in 2018. This data collection method has been successfully used in other studies (Zvolensky et al., 2018). Qualtrics Panels accounts that indicated that they have moderate to severe chronic pain (defined by a single item screener asking if participants had experiences persistent, chronic pain for at least 3 months) and currently use opioid pain medication were sent a notification of the current survey. After brief screening for eligibility, interested participants were directed to the online anonymous survey. Informed consent was provided prior to access of the survey, which was estimated to take 30 minutes to complete. Participants could opt to receive compensation for the study in varying forms (eg, cash-based incentives [ie, gift cards], rewards miles, rewards points etc.). Level of compensation was consistent across all forms, and was typically 20% to 35% of the total cost per study complete ($12.00). The study protocol was approved by the Institutional Review Board at the University of Houston (STUDY00000543).
Participants were 450 (74.67% female, Mage
= 38.59 years, SD = 11.09) adults reporting current opioid use for pain and current chronic pain that persisted for at least 3 months. Additionally, of the 450 participants, 176 participants reported current cannabis co-use (reported cannabis use in the past 3 months). Participants were also eligible if they were between the ages of 18 to 64, and reported moderate to severe pain in the last 4-weeks. Exclusion criteria included being under 18 years of age, a non-English speaker (to ensure comprehension of the study questions), and an inability to give informed, and voluntary, written consent to participant.
The sample was predominately White (77.8%), with 8.7% identifying as Black/African American, 13.1% Hispanic/Latino, 3.3% Native American/Alaska Native, 0.9% Asian/Pacific Islander 2.7% multiracial, and 1.1% other. In terms of education, a little over a fifth (5.8%) did not complete high school, whereas over a quarter of the sample (31.3%) reported attaining a high school diploma, with 22.4% reporting “some college,” and 40.4% having attained an associate degree or higher. The median income bracket was in the range of $35,999 to $49,999.
Analyses were conducted using SPSS version 24. T-tests and χ2 were used to examine differences among sample demographic characteristics. Additionally, analysis of variance analyses were used to examine group differences between people who use opioids alone, and those that co-use opioids and cannabis. Specifically, 10 one way ANCOVAs were conducted to examine mean differences on 10 criterion variables (anxiety, depression, current opioid misuse, severity of opioid dependence, pain intensity, pain disability, and substance use problems [tobacco, alcohol, cocaine, sedatives]), controlling for age, sex, income, and education. Partial η2 was used as a measure of effect size, and estimated marginal mean differences were compared using Least Significant Difference pairwise comparisons. To correct for multiple tests, a Bonferroni corrected P-value of (0.05/10) 0.005 was used.
Examining demographic differences by opioid only vs co-use status, there were significant gender differences, such that there were more women reporting opioid only use (χ2(2) = 15.84,P < 0.001). Additionally, persons reporting opioid only use were significantly older than those reporting co-use (t = 4.01, df = 448, P < 0.001, Cohen's d
= 0.39). However, there were no significant differences for education level (χ2(7) = 6.83, P = 0.45) or income level (χ2(8) = 10.48, P = 0.23) by cannabis use status (Table 1).
The mean difference between people who use cannabis (Estimated Marginal Mean = 2.33, SE = 0.15) and people who do not use cannabis (Estimated Marginal Mean = 1.56, SE = 0.12) was statistically significant, such that co-use was associated with significantly greater PHQ-4 anxiety total scores (Fig. 1 and Table 2).
Those reporting cannabis co-use (Estimated Marginal Mean = 2.50, SE = 0.15) reported significantly elevated PHQ-4 depression total scores than those reporting opioid only use (Estimated Marginal Mean = 1.80, SE = 0.12).
In terms of GCPS pain intensity scores, we observed no differences between those that co-use (Estimated Marginal Mean = 22.33, SE = 0.41) and those that only use opioids (Estimated Marginal Mean = 21.64, SE = 0.33).
For GCPS pain disability scores, we observed no differences as a function of co-use (Estimated Marginal Mean = 28.72, SE = 0.67) and opioid only use (Estimated Marginal Mean = 27.41, SE = 0.53).
Current Opioid Misuse
The mean difference between those that use cannabis (Estimated Marginal Mean = 23.97, SE = 1.17) and those that solely use opioids (Estimated Marginal Mean = 13.88, SE = 0.93) was statistically-significant, such that co-use was associated with significantly greater COMM total scores than opioid only use (Table 3).
Severity of Opioid Dependence
Those that co-use cannabis (Estimated Marginal Mean = 5.41, SE = 0.28) reported significantly elevated SDS total scores compared to those that only use opioids (Estimated Marginal Mean = 3.61, SE = 0.22).
As seen in Table 3, people who co-use reported greater ASSIST scores on tobacco (Estimated Marginal Mean = 15.98, SE = 0.77) than those that only use opioids (Estimated Marginal Mean = 9.07, SE = 0.61).
For ASSIST alcohol involvement scores, people reporting co-use of cannabis and opioids reported greater ASSIST alcohol scores (Estimated Marginal Mean = 13.01, SE = 0.73), relative to those using opioids only (Estimated Marginal Mean = 5.99, SE = 0.58).
In terms of ASSIST cocaine involvement scores, people who use cannabis (Estimated Marginal Mean = 7.63, SE = 0.58) reported significantly elevated ASSIST cocaine involvement scores compared to those who solely use opioids (Estimated Marginal Mean = 0.91, SE = 0.46).
In predicting ASSIST sedative involvement scores, those reporting co-use reported significantly elevated ASSIST sedative scores (Estimated Marginal Mean = 11.77, SE = 0.72) compared to those that use opioids only (Estimated Marginal Mean = 4.92, SE = 0.47).
The current study investigated the association of opioid and cannabis co-use, compared to opioid use only, among adults with chronic pain, a group at particular risk for opioid and other substance use and related problems (Manchikanti et al., 2006). As hypothesized, results indicated that individuals reporting opioid and cannabis co-use also reported significantly greater anxiety, depression, current opioid misuse, opioid dependence, tobacco-related problems, alcohol-related problems, cocaine-related problems, and sedative-related problems. Importantly, these results were evident after controlling for the variance attributable age, sex, income, and education. Of note, the magnitude of the effects (eta2) for all substance-related variables was medium to large, and small to medium for anxiety and depression. For all significant outcomes, however, it is likely that the results have clinical significance. In particular, although anxiety and depression show small to medium effects, even small elevations in anxiety and depression are associated with poor outcomes, particularly among medical patients, pointing to the importance of even small differences (Katon et al., 2007).
Overall, these results are in line with previous research indicating that individuals with substance co-use tend to report elevated psychiatric and other substance-related issues compared to single drug users (Kandel et al., 2001). These results are also consistent with research indicating that medical cannabis use is associated with higher rates of nonmedical opioid use (Caputi and Humphreys, 2018). The findings from the current study uniquely extend past research by providing a comparison between those that solely use opioids and those reporting co-use of opioids and cannabis in relation to several clinically relevant variables, and identifies a unique vulnerability among people who use opioids that may be associated with overall greater morbidity.
Of note, we observed no significant differences with regard to pain intensity or disability between individuals reporting opioid and cannabis co-use and individuals reporting opioid use only. There are plausible explanations to explain these discrepant findings. First, all of the participants in the current study were individuals reporting chronic pain, and therefore, is it possible that there was pain-related ceiling effect. Additionally, it is possible that the use of cannabis did not alter perception of pain. A significant body of work suggests that chronic opioid use is associated with lower pain tolerance (Tompkins and Campbell, 2011), yet the literature on the effects of cannabis on pain tolerance is limited and mixed. For example, one study found that THC alone (an active ingredient in cannabis) did not impact pain tolerance, only when it was combined with morphine (opioid) that there was a decrease in pain tolerance (Naef et al., 2003). Given that all participants in this study were currently using opioids, it is possible that cannabis may have had little impact on the perception of pain.
Potential clinical implications of these findings include that it may be important for clinicians to assess cannabis use prior to initiating opioids for the treatment of chronic pain. The results from this study suggest that cannabis use in the context of opioid use for chronic pain is associated with significantly worse mental health and substance use outcomes, and there may be particular clinical utility in focusing on cannabis use in this population. For people reporting opioid and cannabis co-use, it may also be important to intervene on the cannabis use (ie, Sherman and McRae-Clark, 2016) and associated mental health/substance use problems prior to the initiation of opioids. Additionally, individuals with a propensity to misuse substances may be more attracted to opioid cannabis co-use (Hawkins et al., 1992) and therefore identifying these individuals before treatment for chronic pain may reduce deleterious consequences of combined use. Finally, it may be equally important to closely monitor individuals with chronic pain and comorbid opioid and cannabis use, and future research should examine the longitudinal impact of opioid and cannabis co-use on substance use and pain outcomes.
The current study is not without limitations. First, the data were cross-sectional, prohibiting causal and temporal inferences. Future research should examine group differences in mental health and substance use outcomes over time for individuals with chronic pain, and examine how interactions between cannabis and opioid use may contribute to the observed findings. Second, we did not assess frequency or quantity of cannabis use, and it is possible that amount of cannabis use may influence the variables examined herein. Future research should collect more detailed information regarding cannabis use (eg, amount of THC and/or CBD), and examine the impact of differential use patterns on mental health and substance-related outcomes. Relatedly, due to data collection limitations, geographic data was not collected. Such information would be useful to better characterize the sample in terms of legalization of cannabis for medical or recreational purposes. Third, the data collected in the current study were exclusively by self-report, and therefore, it is possible that the results are due to shared method variance and biases in reporting, particularly for illicit substances. Future studies should employ multi-method assessments of substance use (eg, urine toxicology) and mental health to confirm the findings from the current study. Fourth, although all participants in the current study were individuals reporting opioid use (confirmed by a single item screener), it is not known what patterns of opioid use individuals engaged in, or whether the cannabis was medically prescribed, and future research should conduct a comprehensive assessment to better understand use patterns. Further, it is possible that the type of chronic pain experienced by participants in the current investigation varied in type, etiology, and intensity, and future research, particularly studies conducted online, should gather comprehensive pain information from study participants. Finally, the current study selected individuals who use cannabis after individuals indicated using cannabis in the past 3 months, and it possible that those individuals are not currently using cannabis. Future research should seek to confirm and extend the current findings with people indicating current cannabis use.
Overall, the results from the current study suggest that, among adults with chronic pain, opioid and cannabis co-use (compared to opioids alone) may be associated with greater anxiety and depression symptoms, more severe opioid dependence, and more tobacco, alcohol, and sedative use problems. The large sample may help the current data to generalize to the population of individuals with chronic pain. Overall, the results from this study highlight a vulnerable population of individuals reporting polysubstance use with chronic pain, and indicates the need for more comprehensive assessment and treatment of chronic pain.
Bachhuber MA, Saloner B, Cunningham CO, et al. Medical cannabis
laws and opioid
analgesic overdose mortality in the United States, 1999–2010. JAMA Intern Med
Bar-Lev Schleider L, Mechoulam R, Lederman V, et al. Prospective analysis of safety and efficacy of medical cannabis
in large unselected population of patients with cancer. Eur J Intern Med
Brady KT, McCauley JL, Back SE. Prescription opioid
misuse, abuse, and treatment in the United States: an update. Am J Psychiatry
Brooner RK, King VL, Kidorf M, et al. Psychiatric and substance use
comorbidity among treatment-seeking opioid
abusers. Arch Gen Psychiatry
Buckner JD, Ecker AH, Cohen AS. Mental health
problems and interest in marijuana treatment among marijuana-using college students. Addict Behav
Butler SF, Budman SH, Fernandez KC, et al. Development and validation of the current opioid
misuse measure. Pain
Caputi TL, Humphreys K. Medical marijuana users are more likely to use prescription drugs medically and nonmedically. J Addict Med
Center for Disease Control and Prevention. Today's Heroin Epidemic: More People at Risk, Multiple Drugs Abused (CDC Vital Signs). Center for Disease Control and Prevention. 2015.
Center for Disease Control and Prevention. Multiple Cause of Death Data on CDC WONDER. Atlanta, GA: US Department of Health and Human Services, CDC; 2016.
Cerdá M, Wall M, Keyes KM, et al. Medical marijuana laws in 50 states: investigating the relationship between state legalization of medical marijuana and marijuana use, abuse and dependence. Drug Alcohol Depend
Chou R, Fanciullo GJ, Fine PG, et al. American Pain Society-American Academy of Pain Medicine Opioids Guidelines Panel. Clinical guidelines for the use of chronic opioid
therapy in chronic noncancer pain. J Pain
Chou R, Turner JA, Devine EB, et al. The effectiveness and risks of long-term opioid
therapy for chronic pain
: a systematic review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med
Chu LF, Clark DJ, Angst MS. Opioid
tolerance and hyperalgesia in chronic pain
patients after one month of oral morphine therapy: a preliminary prospective study. J Pain
Daubresse M, Chang H-Y, Yu Y, et al. Ambulatory diagnosis and treatment of nonmalignant pain in the United States, 2000–2010. Medical Care
Deshpande A, Mailis-Gagnon A, Zoheiry N, et al. Efficacy and adverse effects of medical marijuana for chronic noncancer pain: systematic review of randomized controlled trials. Can Fam Physician
Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain
—United States, 2016. JAMA
Edlund MJ, Sullivan M, Steffick D, et al. Do users of regularly prescribed opioids have higher rates of substance use
problems than nonusers? Pain Med
Fiellin LE, Tetrault JM, Becker WC, et al. Previous use of alcohol, cigarettes, and marijuana and subsequent abuse of prescription opioids in young adults. J Adolesc Health
Gossop M, Darke S, Griffiths P, et al. The Severity of Dependence Scale (SDS): psychometric properties of the SDS in English and Australian samples of heroin, cocaine and amphetamine users. Addiction
Grant BF, Stinson FS, Dawson DA, et al. Prevalence and co-occurrence of substance use
disorders and independent mood and anxiety disorders: results from the national epidemiologic survey on alcohol and related conditions. Arch Gen Psychiatry
Hawkins JD, Catalano RF, Miller JY. Risk and protective factors for alcohol and other drug problems in adolescence and early adulthood: implications for substance abuse prevention. Psychol Bull
Hill KP. Medical marijuana for treatment of chronic pain
and other medical and psychiatric problems: a clinical review. JAMA
Hill KP, Palastro MD, Johnson B, et al. Cannabis
and pain: a clinical review. Cannabis Cannabinoid Res
Humeniuk R, Ali R, Babor TF, et al. Validation of the Alcohol, Smoking And Substance Involvement Screening Test (ASSIST). Addiction (Abingdon, England)
Iraurgi Castillo I, González Saiz F, Lozano Rojas O, et al. Estimation of cutoff for the Severity of Dependence Scale (SDS) for opiate dependence by ROC analysis. Acta Esp Psiquiatr
Jané-Llopis E, Jané-Llopis E, Matytsina I, et al. Mental health
and alcohol, drugs and tobacco: a review of the comorbidity between mental disorders and the use of alcohol, tobacco and illicit drugs. Drug Alcohol Rev
Jensen B, Chen J, Furnish T, et al. Medical marijuana and chronic pain
: a review of basic science and clinical evidence. Curr Pain Headache Rep
Kandel DB, Huang F-Y, Davies M. Comorbidity between patterns of substance use
dependence and psychiatric syndromes. Drug Alcohol Depend
Katon W, Lin EH, Kroenke K. The association of depression and anxiety with medical symptom burden in patients with chronic medical illness. Gen Hosp Psychiatry
Kroenke K, Spitzer RL, Williams JBW. The Patient Health Questionnaire-2: validity of a two-item depression screener. Med Care
Kroenke K, Spitzer RL, Williams JBW, et al. Anxiety disorders in primary care: prevalence, impairment, comorbidity, and detection. Ann Intern Med
Leri F, Bruneau J, Stewart J. Understanding polydrug use: review of heroin and cocaine co-use. Addiction
Löwe B, Kroenke K, Gräfe K. Detecting and monitoring depression with a two-item questionnaire (PHQ-2). J Psychosom Res
Löwe B, Wahl I, Rose M, et al. A 4-item measure of depression and anxiety: validation and standardization of the Patient Health Questionnaire-4 (PHQ-4) in the general population. J Affective Disord
Manchikanti L, Cash KA, Damron KS, et al. Controlled substance abuse and illicit drug use in chronic pain
patients: an evaluation of multiple variables. Pain Physician
Martinotti G, Carli V, Tedeschi D, et al. Mono- and polysubstance dependent subjects differ on social factors, childhood trauma, personality, suicidal behaviour, and comorbid Axis I diagnoses. Addict Behav
McCarberg BH, Barkin RL. The future of cannabinoids as analgesic agents: a pharmacologic, pharmacokinetic, and pharmacodynamic overview. Am J Therap
Moss HB, Chen CM, Yi H. Early adolescent patterns of alcohol, cigarettes, and marijuana polysubstance use and young adult substance use
outcomes in a nationally representative sample. Drug Alcohol Depend
Naef M, Curatolo M, Petersen-Felix S, et al. The analgesic effect of oral delta-9-tetrahydrocannabinol (THC), morphine, and a THC-morphine combination in healthy subjects under experimental pain conditions. Pain
Nelson LS, Perrone J. Curbing the opioid
epidemic in the United States: The Risk Evaluation and Mitigation Strategy (REMS). JAMA
Pacula RL, Ringel J, Dobkin C, et al. The incremental inpatient costs associated with marijuana comorbidity. Drug Alcohol Depend
Raft D, Gregg J, Ghia J, et al. Effects of intravenous tetrahydrocannabinol on experimental and surgical pain; psychological correlates of the analgesic response. Clin Pharmacol Therap
Sherman BJ, McRae-Clark AL. Treatment of cannabis
use disorder: current science and future outlook. Pharmacotherapy
Taylor B, Rehm J. When risk factors combine: the interaction between alcohol and smoking for aerodigestive cancer, coronary heart disease, and traffic and fire injury. Addict Behav
Tompkins DA, Campbell CM. Opioid
-induced hyperalgesia: clinically relevant or extraneous research phenomenon? Curr Pain Headache Rep
Von Korff M, Ormel J, Keefe FJ, et al. Grading the severity of chronic pain
Wang H-Y, Friedman E, Olmstead MC, et al. Ultra-low-dose naloxone suppresses opioid
tolerance, dependence and associated changes in mu opioid
receptor–G protein coupling and G(( signaling. Neuroscience
Wasan AD, Butler SF, Budman SH, et al. Psychiatric history and psychologic adjustment as risk factors for aberrant drug-related behavior among patients with chronic pain
. Clin J Pain
Weinberger AH, Desai RA, McKee SA. Nicotine withdrawal in U.S. smokers with current mood, anxiety, alcohol use, and substance use
disorders. Drug Alcohol Depend
Wilsey BL, Fishman SM, Tsodikov A, et al. Psychological comorbidities predicting prescription opioid
abuse among patients in chronic pain
presenting to the emergency department. Pain Med
Zvolensky MJ, Mayorga NA, Garey L. Worry, anxiety sensitivity, and electronic cigarettes among adults. Psychiatr Res
Keywords:© 2019 American Society of Addiction Medicine
cannabis; chronic pain; mental health; opioid; substance use