Learning Objectives/Outcomes: After participating in this CME/CNE activity, the provider should be better able to:
1. Explain the legal, medical, and social aspects of medical marijuana use.
2. List health hazards of marijuana use.
3. Identify the role of medical marijuana in the management of chronic pain.
In recent years, marijuana, also commonly referred to by its plant name, cannabis, has gained much attention, as states have either decriminalized or legalized its use. With the rapid change in public and judicial attitudes, the medical community embraced its role in treating chronic conditions, including chronic pain, perhaps prematurely. Although much consideration has focused on the validity of its medical use, one underappreciated aspect surrounding the issue is the burden or responsibility placed on the treating physician. The lack of consistency on marijuana's legal status, strong scientific evidence, and treatment guideline has led to confusion, whereas best practice is often left to each clinician's judgment.
It is crucial for pain providers to be more knowledgeable on the legal, social, and medical aspects of marijuana, and not to confuse its social acceptance with it being a validated medical therapy. Furthermore, patients might be certified for medical marijuana by other physicians who are not equipped to provide adequate management and follow-up of these patients. By default, the responsibility falls to the treating pain physician, even if that physician does not participate in his or her state's medical marijuana program.
Legal, medical, and social aspects of medical marijuana use must all be considered (Table 1).
Legal Spectrum of Marijuana
With growing evidence of the consequences of overprescription and overuse of opioid medications, physicians continue to search for additional modalities to control chronic pain. Marijuana has emerged as alternative medication that can be used to control chronic pain and in doing so decrease prescription opioid use.
A longitudinal analysis performed by Bradford et al1 demonstrated a significant reduction in opioid prescriptions filled by Medicare Part D patients in states with legalization of marijuana for medical use. Similarly, in states with medical marijuana laws, there is a lower rate of opioid prescriptions in Medicaid patients.2
Marijuana is currently listed as a schedule I drug under the federal government's Controlled Substances Act.3 However, significant efforts have been made to legalize and decriminalize marijuana use in state legislatures.
Decriminalization is the cessation of legal or criminal punishments for the use or procession of a substance, which was first described by the Shaffer Commission in 1972.4 Decriminalization of marijuana alone means that it is still considered a controlled substance; however, one would not be prosecuted with a criminal offense for possession of it (within a certain amount). It is important to note that, in decriminalized provinces, penalties such as fines for possession still exist. Currently, 23 US states and the District of Columbia have decriminalized recreational, nonmedical possession of marijuana5 (Figure 1).
Legalization of marijuana is the process of removing all legal prohibitions.6 Legalization allows its use by the general adult population within a particular context, such as for medical use with a prescription or recreational use analogous to alcohol and tobacco. Since 1996, 33 US states and the District of Columbia have legalized marijuana for medical use.7 In these states, chronic pain is one of the approved indications for its use.8 In addition to medical use, 10 states have legalized marijuana for recreational use.
As more states legalize marijuana for medical and recreational use, it is important to study the implications of the increasing access to it. The prevalence of marijuana use increased for both men (+4.0%) and women (+2.7%) from 2002 to 2014, according to the National Survey on Drug Use and Health.9 Marijuana use is more prevalent among men and the gap continues to widen.9
Multiple studies have demonstrated that, in states with laws that have legalized marijuana use, there is an association with increased use among adults in those states compared with states that never passed these laws.10,11 Martins et al11 continued to show that the greatest increase in use can be seen in adults older than 26 years in states with nonmedical (recreational use).
Increasing use among all populations is thought to be multifactorial and may be attributed to decreased perceived risk of adverse effects of marijuana, perceived ease of access, and decreased consequences for its possession.12 One concern with increasing access to marijuana through liberalization of laws is that more adolescents and youth will become users. However, current literature has demonstrated that there is no significant increase in youth marijuana use (ages 12-17 years) in states with legalization of marijuana for medical or recreational use.13
Although the patient in the case study (see sidebar on p. 4) is fictional, many pain providers are often faced with similar cases daily. In previous years, when marijuana was indisputably considered an illegal drug, handling this situation may have been simple: Before beginning long-term opioid therapy, you would have required Jane to sign an opioid maintenance agreement that included, among other clauses, a stipulation that she would not use any illicit drugs. So, a positive urine screen for tetrahydrocannabinol (THC) would be grounds for you to begin the process of discharging her as a patient.
Things are different now, if the state where you practice has made some legal allowances for marijuana. As states have decriminalized or legalized the medical and even recreational use of cannabis and cannabinoids, it has become a more socially acceptable behavior. When considering the best interest of patients, managing clinical situations similar to Jane's is not so simple, due to multiple implications based on the legal (or illegal) specific status of marijuana in the state where you practice.
This is truly a dilemma for pain practitioners, as we are committed to providing the most empathetic and judicious patient care while adhering to the responsibilities of professional conduct. Currently, we are faced with inconsistencies in statutory legal status, accepted guidelines, and strong scientific evidence. Most often, decisions are left to the individual's best judgment, and herein lies the root of the problem.
Some proponents of cannabis and cannabinoids might suggest that substantial evidence exists for their benefit, especially for conditions such as chronic pain, neuropathic pain, epilepsy, and spasticity.14 However, most of the studies are based on the results of preclinical trials, and human studies are largely observational. Randomized controlled studies also tend to be very small, with sample sizes of fewer than 50 subjects.
The issues surrounding well-powered research include the current illegal status of cannabis on a federal level, strain-dependent cannabinoid varieties, lack of proper dosing guidelines, and various routes of administration. Studies involving patients with fibromyalgia have shown inconclusive results. In one study, nabilone, a synthetic form of delta-9-THC, was administered for 4 weeks. The treatment group achieved a significant improvement in pain and quality of life; however, the difference was less than 30%. Conversely, the treatment group also experienced more side effects. One must question if these results can be interpreted to be clinically significant.15
Case Study
Jane, a 56-year-old woman, has been under your care for the past 3 years. She is struggling with multiple complications related to her type 1 diabetes that have been precariously controlled. Over the years, she has developed Charcot foot with clear deformities of her metatarsal joints, which limits her ambulation. In addition, she suffers from constant neuropathic pain. Her pain has been managed with hydrocodone 30 mg a day. She was tried on multiple antineuropathic agents, but none of them yielded significant improvement. The opioid analgesics help her pain enough to where she can perform simple tasks at home that are essential for independent living. However, she is the first to admit that she is nowhere near comfortable. Because she is a very good patient, she understands the concept of opioid tolerance and dependence, and has never demanded higher doses.
Today, you review her urine drug screen obtained last month and realize that it is consistent for the metabolites of prescribed medication. However, you notice that she is also positive for 11-nor-9-carboxy-delta-9-THC, which is a metabolite of cannabinoids. You cautiously ask her about marijuana use, and she openly admits to it. She tells you that her cousin recommended it and she was pleasantly surprised by its benefit. She uses it mostly at night and says she can finally sleep through the night without being interrupted by the stabbing and burning pain in her feet.
Health Hazards of Marijuana
Cannabinoids can be extracted from the various strains of the marijuana plant and are versatile in formulation. Careful titrations of THC and cannabidiol (CBD) can be custom-made to fit a patient's specific needs. However, illicit marijuana is often smoked and is often cultivated to contain a high concentration of THC to enhance recreational value. Using illicit marijuana can potentially pose harmful effects to many organ systems.
Acute cardiovascular effects include tachycardia, hypertension, and arrhythmias. In a systemic review, Korantzopoulos et al16 showed that cannabis smoking is associated with atrial fibrillation due to adrenergic stimulation favoring myocardial automaticity and microreentry. A sudden catecholamine surge can also lead to the development of ventricular tachycardia.17 In the past, the smoking of cannabis was believed to garner a low coronary ischemic risk. However, recent case reports and observational studies indicate that it may not be so benign. Annual risk of myocardial infarction is near 3%, increasing further with chronic use.18
Smoking cannabis can have deleterious effects on the pulmonary system as well. Although the studies are not as robust as those done on tobacco, enough evidence suggests a correlation between the development of chronic obstructive pulmonary disease and smoking cannabis.19 Inflammatory damage results in loss of epithelial cells and replacement with goblet cells promoting mucus production.20 When considering lung cancer risk, smoking cannabis seems to be an independent risk. Because many cannabis smokers are also tobacco users, results are often confounded. However, when adjusted for nontobacco smokers, the risk of developing lung adenocarcinoma increases for chronic cannabis smokers.21
Substance Abuse and Concomitant Opioid Use
Perhaps a more relevant issue to pain practitioners who may prescribe opioids is the concomitant use of illegally obtained cannabis. The current Centers for Disease Control and Prevention guidelines strongly discourage chronic opioid therapy for nonmalignant pain. This recommendation is based on the lack of evidence of the effectiveness of opiates in treating chronic pain, the increased risk of opioid abuse and misuse, and the contribution to deaths from overdose. The pendulum has definitely swung to where it has almost become taboo to prescribe opioids to patients. Therefore, many pain providers follow strict guidelines on prescribing opiates in situations where they are deemed appropriate. Proper documentation requires a thorough assessment of the patient's pain, a discussion about side effects, risk of overdose, and titration strategies. Under this scrutiny, random urine drug screening cannot be positive for any illegal substances, including marijuana, which, as mentioned, remains a schedule I drug.
Some evidence suggests that marijuana use is associated with opioid misuse in patients on chronic opioid therapy. Multiple studies focus on the prevalence of positive cannabinoid urine tests in patients with chronic pain. In 500 consecutive patients receiving comprehensive pain treatment in Kentucky, including interventional procedures and stable doses of opioids, 11% showed cannabinoids in random urine testing.22 In a Boston academic pain clinic, a retrospective review of random urine drug tests demonstrated cannabinoids in 14.6% of patients.23 When looking at the difference between patients on stable doses of opioids and patients who seek higher doses, the latter group was found to use cannabis at a higher rate. In a prospective study in 2004 looking at 200 patients receiving opioid therapy (100 seeking additional opioids), 25% in the higher-dose seeking group had cannabinoid-positive urine, compared with 15% in the stable opioid dose group.24
The above statistics only display patient characteristics. By themselves, they do not provide significant clinical value except to say that providers should proceed with caution when prescribing opioids. The more valuable aspect is the association of marijuana use with opioid misuse. Current evidence suggests that cannabis use in patients with chronic pain may be associated with opioid misuse. In a large prospective study, Ives et al25 showed this correlation. In their study, opioid misuse was defined as a negative urine test for the prescribed opiate, positive urine tests for opioids or other controlled substances not prescribed by the practice, evidence of opioid prescriptions from multiple providers, prescription forgery, and use of illegal stimulants such as cocaine and amphetamines. The study enrolled 196 patients receiving opioid therapy for greater than 3 months. The mean age was 52 years and 55% were male. Of the enrollees, 62 patients (32%) met the criteria for opioid misuse. It was found that a positive drug test for cannabinoids was a strong predictor of opioid misuse in the following 12 months (33% vs 12%; P = 0.001).
A cannabinoid-positive urine test is also a predictor of substance abuse disorder. Fleming et al,26 in their 2007 survey study of primary care physicians, illustrated that patients who produce cannabinoid-positive urine tests have higher rates of using other substances, with cocaine being the most common drug. Furthermore, it is widely believed that patients who show cannabinoids in their urine display more aberrant behaviors and are more likely to commit opioid contract violation.
In a more recent study, Pesce et al27 reviewed 21,746 urine tests obtained from patients with chronic pain who were taking opioids. The incidence of positive urine tests for cannabinoids was 13%. In this group, 4.6% had tests that were positive for cocaine and 1.07% were positive for methamphetamine. Although these findings do not develop a direct causal relationship, they must be considered in the setting of the current opioid epidemic. A higher prevalence of opioid misuse, other substance abuse, and aberrant behaviors in patients using cannabis must be considered carefully.
At this time, illicit cannabis is not an accepted medical therapy and pain providers should not condone such behaviors. Smoked cannabis presents many challenges. Most illicit strains are designed to be used recreationally with significant mind-altering effects. The goals of comprehensive pain management should include functional and emotional improvement in addition to the lowering of pain level. Using illicit cannabis may not achieve those goals.
Furthermore, as these products are not regulated, it is impossible to verify the content and quality of illicit cannabis. Many contaminants can be imbued during the cultivating process. Many growers use potent pesticides that have been shown to be extremely harmful to humans and animals. As this process is poorly regulated, consumers are at risk of hazardous effects. In addition, improper storage and handling processes can introduce bacteria and fungi into the dried plant mixture.
Kagen et al28 evaluated immunological assays and cultures of marijuana smoked by 28 randomly selected subjects, and the results are striking. Of the 28 subjects, 13 had precipitins against at least 1 Aspergillus antigen. These cultures of marijuana grew pathogenic fungi in various combinations, with Aspergillus being predominant.28 One study subject developed systemic aspergillosis and presented with fatigue, night sweats, and coughing, whereas 6 others experienced allergic reactions after inhalation of marijuana. One interesting discovery was that exposure to these fungal agents can occur without directly smoking marijuana. Exposure to unlit marijuana also resulted in inhalation of fungal spores. This may suggest that exposure may not be just limited to active users but to those around them.
A Role for Cannabis in Pain Care
Medical cannabis has a role in treatment of chronic pain, but requires close monitoring. Despite the lack of significant powered evidence in the current political climate, an abundance of positive anecdotal reports regarding the benefits of medical marijuana for certain pain conditions cannot be ignored. At least, its potential seems very promising. In patients with cancer pain, cannabis has been generally used to suppress chemotherapy-induced nausea and improve appetite. In this population, however, evidence exists to support the use of marijuana for pain relief as well. In a randomized controlled trial, patients with cancer with inadequate pain control, despite opioid therapy, were given nabiximols (a mucosal spray of THC and CBD mixture).29 Pain relief was compared with pure THC and placebo. It showed that patients on nabiximols had greater than 30% pain relief compared with their baseline, and the effects were significantly better than in either THC or placebo groups.
For nonmalignant pain, medical cannabis shows the most benefit in patients suffering from neuropathic conditions. A randomized controlled trial evaluated the efficacy of nabiximols on patients with brachial plexus injury.30 A total of 48 patients were given the study drug, THC, or placebo. Although the decrease in pain score did not quite reach the statistical significance, a strong trend was demonstrated in the nabiximols group. The main reported side effects were sedation and drowsiness.
In another randomized controlled trial, cannabis at various doses was studied against placebo in patients with HIV with painful neuropathy.31 Patients on cannabis reported significantly better pain control compared with those on placebo, and 46% of the patients showed greater than 30% reduction in their pain.
For treating somatic pain, cannabis shows promising results in patients with rheumatoid arthritis and fibromyalgia. A study evaluating the efficacy of nabiximols on patients with rheumatoid arthritis showed significant improvement in pain with movement, at rest, and during sleep.32 Mixtures of THC and CBD show greater benefit compared with either one alone.33
A majority of studies are limited by small sample size, but it is reasonable to conclude that cannabis could have a distinct role in treating certain chronic pain conditions. It is equally important to monitor and document patients' functional improvement. It is prudent to ask patients what activities they are able to perform due to cannabis therapy. Many patients will report significant functional improvement, and it should be indicated as such on their records. As part of comprehensive pain treatment, the importance of optimizing social engagement and interpersonal relationships cannot be understated. Secondary to experiencing less pain, a patient improves the ability to develop better communication with family members, attend more functions, and achieve higher performance at work.
It is important for pain physicians to monitor for adverse effects of cannabis. Unfortunately, patients are often carelessly certified for medical marijuana by physicians who are not equipped to provide adequate management and follow-up of these patients. By default, the responsibility is transferred to and should be assumed by the treating pain physician.
Marijuana and Drug Interactions
A concerning, but underappreciated, aspect of concomitant cannabis therapy is its interaction with other medications (Table 2). Induction or inhibition of enzymes such as CYP450 can be responsible for drug-drug interactions. Although enzyme inductions may take severe days to present clinically, inhibitions can occur much more rapidly. A recent systemic review indicates that P-450 is affected by multiple cannabinoids such as THC, CBD, and cannabinol.34 THC and CBD are also CYP1A2 inducers and function as inhibitors of CYP3A4. Ultimately, they may affect the metabolism of other drugs dependent on these pathways.
Wilens et al35 demonstrated the interaction of THC with tricyclic antidepressants. This case series report highlights 3 adolescent patients on nortriptyline or desipramine who developed tachycardia and delirium after smoking marijuana. These effects are thought to be mediated by the anticholinergic effects of tricyclics, which are potentiated by adrenergic properties of THC. A similar event was seen in a patient taking fluoxetine.36 Although the exact mechanism is still unknown, it is important to recognize these potential interactions and monitor patients-and educate them.
Cannabis-opioid interactions are thus far poorly studied overall. When both medications are administered together, they seem to show additive effects in pain relief. However, it is not well understood whether cannabis could potentiate opiate receptors responsible for life-threatening side effects such as apnea. Manini et al37 conducted a safety and pharmacokinetic study of oral CBD and IV fentanyl given simultaneously. The authors concluded that coadministration of both agents is safe and well-tolerated in healthy human volunteers. The serum levels of these drugs were not affected by one another. However, it is well understood that THC is a potent central nervous system suppressant, and full caution should be exercised when THC is taken in combination with other central nervous system depressants such as benzodiazepines, anticonvulsants, barbiturates, and opioids.
Medical Marijuana and Preexisting Psychiatric Conditions
A causal relationship between cannabis use and mental illness has not been fully established. Notably, many patients with chronic pain have comorbid psychiatric conditions such as depression, anxiety, panic disorders, and psychosis. There is some evidence that cannabis use can potentiate or unmask psychosis and worsen psychological conditions.38 Therefore, pain providers should be aware of the impact medical marijuana could have in this subpopulation. Symptoms of paranoid delusions and hallucinations after smoking cannabis can outlast the duration of intoxication in patients with no previous history of psychosis. For patients who are diagnosed with schizophrenia, use of cannabis can provoke acute psychosis.
High rates of depression and anxiety are associated with patients with chronic pain. Up to 54% of patients with chronic pain report coexisting depression, whereas anxiety disorder affects close to 50%.39 Many more patients exhibit depressed mood without meeting the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria for diagnosis. According to addiction literature, substance abuse disorder is closely linked with depression. However, it is unclear whether depression is initiated by cannabis or maintained by it. Some medical cannabis research actually shows improvement in depressive symptoms when patients are on such therapy. In a study exploring rates of depression in patients with chronic pain on chronic opioid or medical cannabis therapy, a much higher rate of depression was observed in the former group.40
Conclusion
Chronic pain is a multifactorial process, and every patient presents a unique set of challenges. Because of the opioid epidemic, more traditional approach to pain management is under extreme scrutiny. Secondarily, many providers and patients are constantly searching for new and alternative therapeutic options. Medical cannabis has gained much attention as many states are legalizing it for medical purposes, but it brings its own share of serious considerations. Scientific evidence leans toward marijuana being clinically useful for the treatment of chronic pain and safe for term use. However, clear monitoring parameters are not developed, and as with any other medical intervention, potential for adverse effects, misuse, and addiction exists. Management of the patient with chronic pain who also uses or desires to use marijuana is outlined in Figure 2.
Because the US Drug Enforcement Administration maintains cannabis and cannabinoids as a schedule I substance, opportunity for scientific research in the field has been limited. Most of the studies are either underpowered or not controlled. It is difficult to translate animal studies to clinical settings, as well. Robust clinical research is needed to ensure effective, yet safe, use of medical cannabis. Studies should seek to identify optimal dosing strategies, appropriate clinical conditions, long-term effects including abstinence syndrome, and which patients are vulnerable to adverse effects.
First and foremost, smoking street cannabis should not be tolerated. Its lack of purity, abuse potential, health risks, and lack of regulation cannot overcome the potential benefit. For conditions that are known to respond to cannabis therapy, if the state allows medical cannabis, patients must be encouraged to be certified and registered to the state. For those who do not qualify or have conditions that may be exacerbated by its use, pain providers should discuss the risks and develop alternative treatment plans and seek help from substance abuse specialists, if recognized.
For patients on medical cannabis therapy, its benefit and side effects must be closely monitored and documented. Reduction in pain score and improvement in function are important measures of successful therapy. Key elements of considerations are abilities to perform self-care, engage in social interactions, and develop meaningful social interactions. Achievements of nominal value to others may have tremendous meaning for their lives. Another challenge for pain providers is to be knowledgeable of potential adverse effects of medical cannabis and advise patients appropriately. Close attention should be focused to identify oversedation, drug-drug interactions, exacerbation of preexisting psychiatric symptoms, and, of course, abuse potential.
Currently, the lack of scientific evidence and proper guidelines calls for more vigorous research in the future. In addition, more physician education is essential to minimize any insecurity and even distress imposed on pain providers who assume the responsibility of managing patients with chronic pain. Furthermore, a multidisciplinary team approach should include pharmacists, psychiatrists, addiction specialists, and primary care providers. This team approach is the cornerstone of safe, yet effective, management of patients with chronic pain with medical cannabis therapy.
References