Evidence of Cannabinoids in Pain
Cannabinoids and opioids have had worldwide use for millennia. They were renowned for analgesic, sedative, and euphoriant properties. Both were typically smoked in individual or community settings such as opium dens and hash clubs. Both have come under legislative scrutiny in the United States and elsewhere [1]. Opioids are generally accepted as valid medical agents (DEA Schedule II), while marijuana is generally illegal (DEA Schedule I).
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Do opioids have limitations in their analgesic properties?
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How addictive are opioids when used for analgesia short and long term?
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What are the analgesic properties of the cannabinoids?
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How addictive are the cannabinoids?
- 5.
Are opioids and cannabinoids potentiators of each other’s analgesia?
- 6.
Do cannabinoids “protect” from opioid addiction?
- 7.
Is there any role for “medical marijuana”?
1. Do Opioids Have Limitations in Their Analgesic Properties?
Opioids and opiates have a generally accepted clinical place in the comprehensive management of acute and cancer pain. Their effect is primarily from inhibiting neurotransmitter release and activating descending inhibition within the nervous system at multiple levels. Their pharmacology is well described in standard textbooks and is beyond the scope of this chapter [4]. When used for acute pain, opioids produce significant dose-dependent adverse effects including nausea and vomiting, urinary retention, respiratory depression, hyperalgesia, pruritis, acute tolerance, and chronic dependence. Opioids may have greater effect depending on patient genotype, physiology, route of administration, and the type of pain. There is usually no ceiling effect of these effects or adverse effects. However, clinical adverse effects may limit dosage.
A significant contributor to the misuse of opioids has been liberal prescribing practices related to acute pain. The longer the duration of the “acute” prescription, the more likely the subsequent misuse of the opioid medication. According to the Centers for Disease Control and Prevention (CDC) guideline [5], when opioids are used for acute pain, clinicians should prescribe the lowest effective dose of immediate-release opioids. They should prescribe no greater quantity than needed for the expected duration of pain severe enough to require opioids. Three days or less will often be sufficient; more than 7 days will rarely be needed according to the CDC. In 2016, Mudumbai et al. looked at postsurgical opioid use in US Veterans. The median duration for stopping opioids after surgery in opioid-naïve individuals was 15 days. For any patient on regular or intermittent opioids before surgery, the median day for stopping was much longer [6].
However, the role of opioids in the management of chronic and neuropathic pain is under increasing scrutiny [1]. Part of this renewed interest is the result of increasing knowledge and precision surrounding chronic and neuropathic pain.
Chronic primary pain
Chronic cancer-related pain
Chronic postsurgical pain
Chronic posttraumatic pain
Chronic neuropathic pain
Chronic secondary headache
Chronic orofacial pain
Chronic secondary visceral pain
Chronic secondary musculoskeletal pain
This apparent heterogeneity of a previously simplistic diagnosis indicates that there can be no rational guideline for “chronic pain management.” Therefore, no meaningful guidelines can be formulated for overall management of chronic pain.
The long-term use of opioids in chronic pain was generally believed to be safe and efficacious. The “opioid crisis” has focused attention and questions on this assumption [8–10]. There is increasing evidence that opioids may not be as effective for long-term use as previously believed. A recent systematic review and meta-analysis of opioids for chronic noncancer pain [11] concluded that opioid use was associated with statistically significant but only small but probably not meaningful clinical improvements in pain and physical functioning compared with placebo. Comparisons of opioids with non-opioid alternatives suggested that the benefit for pain and functioning may be similar for both approaches.
The data above refers to full opioid agonists. Partial agonists have a ceiling effect in both analgesia and adverse effects [4]. Their long-term use for pain conditions seems less well documented than for management of opioid misuse situations [12].
2. How Addictive Are Opioids when Used for Analgesia Short- and Long-Term?
A recent publication by the National Institute on Drug Abuse [13] stated that in the late 1990s pharmaceutical companies reassured the medical profession that patients would not become addicted to prescription opioid pain relievers. This is felt to be a major factor in increased prescription rates for opioids.
The NIDA stated in January 2019 that more than 130 people die each day in the United States after overdosing on opioids. These include prescription analgesics, but perhaps more importantly heroin and fentanyl.
Roughly 21–29 percent of patients prescribed opioids for chronic pain misuse them.
Between 8–12 percent develop an opioid use disorder.
An estimated 4–6 percent who misuse prescription opioids transition to heroin.
About 80 percent of people who use heroin first misused prescription opioids.
It should be noted, however, that these data are from individual publications, some retrospective, and not from reviews or meta-analyses. They should be interpreted with caution. Nevertheless, they might appear to have some medicolegal appeal in an adversarial situation.
It must be concluded that there is a real risk in prescribing and using opioids for chronic pain [14. 15].
Know that opioids are not first-line therapy for chronic pain
Discuss risks, benefits, and availability of non-opioid treatments with patients
Establish and measure goals for pain and function
Emphasize patient-centeredness and individualized care
Evaluate risk factors for opioid-related harms specific to the individual
Avoid concurrent benzodiazepine and opioid prescribing
Prescribe opioids only in needed quantities and durations
Initiate opioids at the lowest effective dose with frequent follow-up and monitoring
Ensure opioids, when indicated, are part of a comprehensive, multimodal pain treatment plan
Use prescription drug monitoring programs and urine drug testing to monitor patient adherence to the treatment plan
Reduce opioid dose or taper and discontinue if risks outweigh benefits or if benefits do not outweigh harms
Arrange treatment for opioid use disorder if indicated
Inflexible application of recommended ceiling or prescriptions as hard limits
Abrupt opioid taper or cessation in physically dependent patients
Lack of availability and coverage for recommended comprehensive multimodal care
Difficulty of opioid use disorder diagnosis and barriers to treatment
Underutilization of naloxone
Incomplete data in reporting of overdose death statistics
Appropriate opioid tapering
Prescription dose and duration limits
Toward comprehensive multimodal care
Protecting patients from unintended consequences
Toward naloxone and opioid use disorder treatment optimization
This panel report, if widely accepted, will take time to be tested and have results published. In the meantime, it should act as a valuable resource for practitioners contemplating the initiation or maintenance of long-term opioid therapy for chronic pain patients.
Prescribing guidelines for chronic opioids have been promulgated by numerous other entities, such as the Federation of State Medical Boards [17], Drug Enforcement Administration, Colorado Department of Regulatory Agencies [18], Veterans Administration/Department of Defense [19], and the Washington State Agency Medical Directors’ Group [20]. These guidelines carry the same general message as the CDC – be cautious and document carefully.
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Failure to produce adequate analgesia
- 2.
Development of tolerance
- 3.
Development of physiologic dependence or pseudoaddiction
- 4.
Development of unacceptable adverse effects
- 5.
Evidence of misuse of opioids or other substances
- 6.
Evidence of non-compliance with agreed-upon interventions (such as physical therapy, work hardening, urinalyses, etc.)
- 7.
Problematic use of other substances (alcohol, cannabis)
The patient must not be abandoned but must have suitable transitions to alternative therapies, perhaps even under the care of a different healthcare provider.
3. What Are the Analgesic Properties of the Cannabinoids?
The US Department of Justice Drug Enforcement Administration was petitioned on December 17, 2009, for removal of marijuana from Schedule 1 of the Controlled Substances Act [21]. This Schedule contains drugs with no currently accepted medical use and a high potential for abuse. Some examples of Schedule I drugs are heroin, lysergic acid diethylamide (LSD), marijuana (cannabis), 3,4-methylenedioxymethamphetamine (ecstasy), methaqualone, peyote, and psilocybin.
This reschedule application was denied by a letter dated July 19, 2016. The Department considered the available literature and tabulated 11 reference papers in the report.
The drug’s chemistry must be known and reproducible.
There must be adequate safety studies.
There must be adequate and well-controlled studies proving efficacy.
The drug must be accepted by qualified experts.
Scientific evidence must be widely available.
The FDA has not approved cannabis for the treatment of any disease or condition (FDA FAQ accessed 7/18/2019). It has approved Epidiolex® for certain seizures and Marinol® and Syndros® (dronabinol) for nausea and anorexia under certain conditions. Cesamet® (nabilone) is also approved.
This makes both animal and human studies very difficult in the United States.
Pharmacodynamics
These papers point out that cannabis and cannabinoids act on multiple pain targets. These include both central and peripheral targets, not only CB1/CB2 receptors but also GPCR55 and other GPCRs such as opioid and serotonin receptors. There are several nuclear receptors and transient receptor (TRPV1) channels which may interact. TRPV1 and CB1Or CB2 may be co-localized at peripheral and/or central neurons. Interaction between these receptors is being demonstrated as a component of pain modulation.
Phytocannabinoids
Although the main psychoactive component of the cannabis plant is delta-9-tetrahydrocannabinol, there are more than 100 different cannabinoids so far identified.
Cannabidiol (CBD) is a non-psychoactive analog of THC, and the other main putative active compound. The FDA has approved this as Epidiolex® for treatment of two rare and severe forms of epilepsy (Lennox-Gastaut Syndrome (LGS) and Dravet Syndrome (DS)) [27].
The FDA notes liver toxicity as a potential adverse effect of CBD. In controlled studies on Epidiolex®, the incidence of ALT elevation 3 times that of normal values was 13%, compared with 1% for placebo in patients with LGS and DS. As such, periodic LFT monitoring is suggested. The most common cause for discontinuing the medication was LFT elevations. Other common adverse reactions include somnolence, reduced appetite, diarrhea, fatigue, malaise, asthenia, rash, insomnia, sleep difficulty, and infection. At this time, there are no documented cases reported of fatal cannabis overdosage. It is clear that more and better clinical studies are needed to demonstrate whether CBD has clinically significant analgesic effects and to define adverse effect profiles.
Endocannabinoid System
Current evidence suggests that the CB1 and CB2 are involved in multiple regulatory functions:Learning and memory
Mood and anxiety
Drug addiction
Feeding behavior
Modulation of pain and certain cardiovascular functions
The CB1 receptor is localized in regions of the peripheral and central nervous systems where pain signaling, transmission, and modulation occur.
The CB2 receptor is predominantly peripheral and appear to inhibit cytokine/chemokine inflammatory processes. It may also stimulate the release of beta-endorphin from keratinocytes.
Synthetic Cannabinoids
Dronabinol is the oral preparation of THC. It is approved for nausea and vomiting associated with chemotherapy and anorexia associated with AIDS.
Nabilone is a synthetic structural analog of THC, with similar approved indications. However, studies of these have shown minimal, if any benefit in reducing morbidity or mortality [28].
The off-label use of these medications for pain management is likely to be expensive and ineffective. No reliable data exist.
Cannabinoids in Animal Models of Pain
Animal data show that cannabinoids are effective in some models of acute/nociceptive pain, chronic neuropathic pain, and chronic inflammation. Certain animal cancer pain models also suggest cannabinoid efficacy. On the other hand, Delta-9-THC has been shown to preferentially increase dopamine transmission in the shell of the nucleus accumbens, similar to heroin [29]. Though this observation was found Sprague-Dawley rats, it suggests activation of dopamine transmission may be involved in Delta-9-THCs affective and motivational properties. In addition, activation of specific cannabinoid receptors may activate dopamine transmission in the nucleus accumbens through activation of an endogenous opioid system affecting Mu1 opioid receptors of the ventral tegmental area. Neuroimaging studies have suggested hypodopaminergia with regular cannabis use, which may reduce reward sensitivity and amotivation [30].
It has been difficult to translate animal data to the clinical situation.
Cannabinoids in Clinical Pain Research and Therapy
It is expected that human volunteer subjects will respond to experimental pain stimuli quite differently than patients with diagnosable pathological pain generators, whether acute or chronic [31]. Of note, endogenous opioids, endocannabinoids, and dopamine transmission may be involved in the placebo effect. Enhanced dopamine release in the nucleus accumbens correlated to placebo responsiveness and financial reward [32]. More recent evidence suggests that the endocannabinoid system and the endogenous opioid system contribute to analgesic placebo response [33].
Cannabinoids and Acute Clinical Pain
Data are presently inconclusive on the efficacy of cannabinoids in acute clinical pain, whether postoperative or traumatic [34]. There may be a window of efficacy, with “moderate” doses being somewhat effective.
There is evidence that chronic cannabinoid use increases opioid requirements after polytrauma [34].
Cannabinoids and Clinical Neuropathic Pain
Several systematic reviews of cannabinoids and neuropathic pain have shown moderate strength evidence of potential benefit, but better research is necessary to clearly define dose-response characteristics [35, 36].
Nabiximols (Trade Name Sativex) and Cancer Pain
Sativex (50% THC, 50% CBD) had been thought to improve pain in advanced cancer and to be associated with decreased opioid use. However, data are presently inconclusive. Sativex has failed two Phase III clinical trials in cancer pain patients who maximized opioids [37].
Cannabis and Chronic Pain
Although cannabis appears to be widely used for chronic pain management, there is often little medical input [37, 38]. There are a few data supporting cannabis safety and efficacy, despite more than 30 US states enacting “medical marijuana” legislation [39]. This deficit is widely recognized [40].
Cannabis is rarely the first drug chosen by the patient for the management of pain. Pain can obviously occur in chronic cannabis users, who revert to usual medical pain management.
It was also hoped that medical marijuana legislation would produce a reduction in community use of prescribed opioids [41]. This has not become evident. It was also hoped that the legalization of recreational marijuana would mitigate the opioid crisis. This has also not occurred [42]. The data showed that in 2017, among 70,237 drug overdose deaths, 47,600 (67.8%) involved opioids. From 2013 to 2017, synthetic opioids (heroin and illegally manufactured fentanyl) contributed to increases in drug overdose death rates in several states, including Washington and Colorado.
4. How Addictive Are the Cannabinoids?
Cannabis use disorder is a diagnosis in DSM-5 under Substance-Related and Addictive Disorders. DSM-5 eliminated Cannabis Abuse and Cannabis Dependence in lieu of a single category, which includes all of the problems previously discussed in the separate categories. The diagnosis is made by defining at least 2 of 11 criteria occurring within a 12-month period. Further, the severity of the problem can be indicated as mild, moderate, or severe, based on the number of symptoms exhibited.
It is worth noting that as potency of cannabis products has increased, so has progression to cannabis use disorders [43]. For further details, please refer to the corresponding chapter in this book.
5. Do Cannabinoids and Opioids Potentiate Each Other’s Analgesia?
A multi-institutional pilot study of marijuana uses and acute pain management following traumatic injury suggested that marijuana use may affect pain response to injury by requiring greater use of opioid analgesia. This effect was less pronounced with other drugs [34].
6. Do Cannabinoids “Protect” Users from Opioid Addiction?
This question has been difficult to address for reasons given earlier. The definitive review of the current state of knowledge appears as a draft dated June18, 2019, by Larkin PJ and Madras BK [2].
Individuals using marijuana for pain relief do not exhibit a reduction or elimination of opioid use [2]. Indeed, there is some evidence that cannabis users increase their opioid use without obtaining increased pain relief. In another study cannabis users appeared to be at increased risk of prescription opioid misuse [38].
In addition, the concomitant use of marijuana and opioids appears to interfere with treatment of opioid use disorder [44, 45].
7. Is There Any Role for “Medical Marijuana”?
No smoked substance can be considered a drug.
No plant can be considered a drug.
Active ingredients cannot be defined or quantitated.
It is a Schedule I substance.
Volume of smoke/aspirate
Depth of inspiration
Duration of inspiratory hold
These obviously cannot be standardized from one individual to another.
Because of the issues listed above and elsewhere in this paper, it does appear that the science presently fails to support the concept of “medical marijuana” [46].
Cancer, HIV, multiple sclerosis, epilepsy or other seizure disorder, or spasticity disorders.
Intractable pain, limited for the purpose of this chapter to mean pain unrelieved by standard medical treatments or medications
Glaucoma
Crohn’s disease
Hepatitis C with debilitating nausea or intractable pain
Diseases, including anorexia
Chronic renal failure requiring hemodialysis
Posttraumatic stress disorder
Traumatic brain injury
Medical doctor (MD)
Physician assistant (PA)
Osteopathic physician (DO)
Osteopathic physician assistant (DOA)
Naturopathic physician
Advanced registered nurse practitioner
Complete health history
Comorbidities
History of substance abuse
Complete physical examination
Review of medications
Written treatment plan
Treatment options
Determination of need for marijuana
Risks of marijuana
Periodic reevaluation
Maintenance of health records
Written consent
Such requirements are consistent with prescribing regulations and practice guidelines for opioids. They should surely discourage both “pill mills” and “pot shops.” Time will tell, but more than 39,000 medical marijuana cards have been issued to Washington state residents by April 25, 2019. There seem to be no data on the impact on any aspect of public health of this legislation. Opioid prescriptions and overdoses have continued to rise nationally [42] in an apparently inexorable manner, with no respite from either recreational or medical marijuana legislation.
The role of patient advocacy groups in the opioid/cannabis crisis is unclear. There was no question that these groups were strong supporters of the concept of pain as the “fifth vital sign” [48]. They also helped improve access to opioids for acute, chronic, and terminal pain. There is a question, reflected in opioid overdose mortality data, that the pendulum might have swung too far in the direction of permissive prescribing of opioids [48, 49]. Again, there are few data available.
The American Chronic Pain Association (www.theapca.org) has published a thoughtful, scientifically valid informational booklet for patients and, I hope, providers. It contains a very useful section on opioids (pp. 75–102). This should be required reading for patients and prescribers of opioids [3].
Summary
Cannabis and opiates have been used for millennia for their euphoriant effects. However, with the advent of cannabinoids and opioids within the last century, there has been increasing attention paid to the putative analgesic effects.
Cannabis use disorder has increased in the United States. Many states (but not the federal government) have enabling legislation. Growth of more potent strains of cannabis has increased. Cannabis itself does not produce analgesia and paradoxically might interfere with opioid analgesia. Cannabis users have been shown to increase their opioid use without an increase in analgesia.
Opiates and opioids have physiological effects, including analgesia, respiratory depression, nausea and vomiting, hyperalgesia, pruritis, and tolerance and dependence. These effects are of relatively minor significance and controllable in acute use for analgesia. However, when tolerance and dependence occur, the analgesic effect is also reduced, and adverse effects become more important.
Opioid use disorder and overdosage have become significant public health problems in the United States. There are opioid prescribing guidelines at federal and state levels. Despite these, opioid overdoses account for nearly 70% of drug overdose deaths (47,600 in 2017). A significant proportion of these individuals were first exposed to prescription opioids.
It is clear that there needs to be more basic research on cannabinoids and opioids. It is also clear that the clinical use of these chemicals should be based on a more rational scientific basis than is available at present.
This chapter cannot address the particular medicolegal circumstances in each state. Each practitioner who has prescribing or authorizing capability for cannabinoids and/or opioids must conform to their own state guidelines. It must be recognized that cannabis is a federal Schedule I substance and illegal in that jurisdiction. State guidelines might therefore be in conflict with federal guidelines.