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15 Articles in Volume 16, Issue #6
Osteoarthritis and Central Pain
Uncovering the Sources of Osteoarthritis Pain
The Synergistic Effects of Mood and Sleep on Arthritis Pain
Nonsurgical Rx of OA: Analyzing the Guidelines
Osteoarthritis Disability Is Often Underestimated By Rheumatologists
10 Pain Medication Myths
The Use of Medical Marijuana for Pain in Canada
6 Common Concerns Regarding Medical Marijuana
What Pain Specialists Need to Know About Medicinal Cannabis
Applying Kinesiology as a Multipronged Approach to Pain Management: Part 2
Practical Guide to Adding Recreation Therapy Into Pain Management
A Novel Treatment for Acute Complex Regional Pain Syndrome
Genetic Testing in High-Dose Opioid Patients
No More “Fifth Vital Sign”
Letters to the Editor: Disc Herniation, SCS, Arachnoiditis, Tapering Opioids

The Use of Medical Marijuana for Pain in Canada

Medical marijuana (cannabis) is gaining wide acceptance as an effective pain control remedy by physicians in both Canada and in the United States.

Cannabis sativa (cannabis) has been used as a medicinal agent for almost 5,000 years in traditional Eastern medicine. Its introduction into Western medicine took place in 1841 as a result of  the work of William O’Shaughnessy, an Irish physician who encountered “Indian hemp” in Calcutta. By the late 19th century, pharmaceutical companies in the Americas were producing medical cannabis in the form of cannabis-based extracts, tinctures, cigarettes, and plasters.1,2 These agents were mainly indicated for a wide range of conditions, many related to pain.3,4

In 1892, a leading Canadian internist, Sir William Osler, wrote in The Principles and Practice of Medicine that “Cannabis Indica is probably the most satisfactory remedy for migraines.”5 Despite these benefits, the medical use of cannabis fell from favor, and in the 1930s and 1940s was widely banned around the world.1 More recently, the medical use of cannabis has re-entered the market in several countries for the treatment of a variety of conditions, including pain.6,7

 

Support for Medical Cannabis

There appears to be a surge in evidence supporting the medicinal use of cannabis, in part due to patients reporting significant pain relief and reduction in the use of other medications, including opioids. In a large survey of medical cannabis users in Arizona with chronic pain, 77% of fibromyalgia patients, 63% of patients with arthritis, and 51% of patients suffering from neuropathic pain reported experiencing “a lot” or “almost complete overall relief” of their painful condition.8 These were subjective measures (no numeric or visual-analogue rating scales were applied before or after used).

Reduced usage of other medications, as described as “a little or much less frequency,” was found in 94% of patients with fibromyalgia, 81% of arthritic patients, and 61% of patients with neuropathy who used medical cannabis. Moreover, 75% of medical cannabis users who experienced opioid dependency reported a lot or almost complete overall relief.8 These findings highlight the wide range of clinical uses for medical cannabis, as well as the value of such studies at a time where evidence from controlled clinical trials is still emerging.

In the United States, the federal government still classifies cannabis, along with heroin, as a Schedule I drug; that is, as having a high potential for abuse and no recognized medical use. At the same time, 25 states and the District of Columbia have legalized marijuana for medical or recreational use.9 Each state has its own laws for recommending, dispensing, and possessing medical marijuana. [Editor’s Note: The Drug Enforcement Agency is weighing whether to downgrade its classification of medical marijuana from Schedule I to Schedule II.]

Cannabis and Pain: Mechanistic Considerations

The cannabis plant contains many biologically active components, including over 60 cannabinoids.10 There are 3 types of cannabinoid molecules that bind to cannabinoid receptors. These include: phytocannabinoids, which are obtained from the cannabis plant; synthetic cannabinoids (such as nabilone [Cesamet], a synthetic nitrogen analogue of delta-9-tetrahydrocannabinol [THC]); and endogenous cannabinoid receptor ligands, also known as endocannabinoids. THC, a phytocannabinoid, is the primary psychoactive
component found within cannabis that has been shown to have analgesic effects (Figure 1).11

Further, there is increasing evidence  highlighting other medicinal properties  for other phytocannabinoids. In particular, cannabidiol (CBD), a nonpsychoactive molecule, has been shown to have anti-inflammatory12 and analgesic13,14 properties. THC and CBD are biosynthesised from a common precursor as delta-9-tetrahydrocannabinoilic acid (THCA) and cannabidiolic acid (CBDA), respectively,15 and require heat or extraction to undergo decarboxylation to produce THC and CBD properties.16 Other phytocannabinoids with potential therapeutic effectss include cannabigerol, cannabichromene, cannabinol, cannabidivarin, and tetrahydrocannabivarin (Figure 2, above).17

THC mimics the action of the endogenous cannabinoids anandamide and 2-arachidonylglycerol (2-AG).18 Both THC and anandamide are partial agonists of cannabinoid type 1 (CB1) receptors,16,18 which are primarily expressed in the central nervous system, particularly in areas related to pain, such as the spinal trigeminal nucleus, amygdala, basal ganglia,19 and the peri-aqueductal gray.20,21

At the cellular level, the central nervous system’s expression of CB1 receptors are localized on the terminals of presynaptic neurons.22 The endocannabinoids that bind to them act as retrograde signaling agents; that is, they are synthesized postsynaptically and move backward across the synapse to inhibit presynaptic neurotransmission.23 It is believed that THC induces analgesia by inhibiting neurons activated by pain in regions associated with nociception by binding presynaptic CB1 receptors (Figure 3).

As mentioned previously, CBD has intrinsic analgesic and anti-inflammatory properties13,14,24 and antagonizes several adverse effects of THC, including sedation,16,25 tachycardia,16,26 and anxiety.27 CBD also ameliorates the psychoactive effects of THC,27 an issue for many medical cannabis patients. It achieves this by slowing the conversion of delta-9-THC to the more psychoactive
delta-11THC. Unlike THC, CBD has low affinity for CB1 receptors28 and exerts analgesic actions by binding multiple proteins related to pain. For example, CBD has been shown to bind TRPV1 (Transient Receptor Potential Cation Channel, Subfamily V, Member 1), to mediate its desensitization, and to inhibit inactivation of anandamide,28 both of which contribute to analgesia. CBD is a potent anti-inflamatory agent and may indirectly induce analgesia by limiting inflammation at the site of injury.12

Clinical Evidence

While there is substantial preclinical evidence showing that smoking cannabis is beneficial in treating chronic pain conditions, including osteoarthritis, rheumatoid arthritis, fibromyalgia, and cancer, no randomized controlled trials (RCTs) have been carried out for these conditions.29 However, to date, there have been 5 RCTs that have evaluated the analgesic efficacy of cannabis for patients with neuropathic pain.30-35

These studies included a meta-analysis that examined the analgesic efficacy of cannabis with THC concentrations ranging from 3.5% to 9.4% against that of a placebo.35 [Editor’s Note: Typical strains of medical marijuana that are available for study in the US through the National Institute on Drug Abuse, University of Mississippi farm, range from 1% to 7%.]

The study classified those who showed a greater than 30% improvement in chronic pain score following cannabis dosing as “responders,” creating a useful dichotomy for comparing response data between interventions. Based on this approach, the authors determined that inhaled cannabis results in a number needed to treat (NNT) to reduce chronic pain by greater than 30% of 5.6. This NNT value rivals currently available treatments for chronic neuropathic pain,36 which are typically well above 8.35,37-39 In addition, the studies showed that the pain relief provided by cannabis was dose-dependent, with higher THC content producing increased analgesia.This finding provides further support for the notion that cannabis is an effective analgesic for chronic neuropathic pain.

Pharmacokinetics

To date, pharmacokinetic studies of cannabinoids have predominantly focused on the bioavailability of inhaled THC.40,41 However, the bioavailability of THC varies considerably in studies, likely due to differences in factors such as breath-hold length, source of cannabis material, and method of inhalation.40,41 Typically, 25% to 27% of the inhaled THC is delivered to the systemic circulation.42,43

The onset of action for inhaled cannabis is more rapid than that for cannabis consumed orally—observable effects are within minutes from smoking versus hours with the oral route.44-46 Additionally, a lower peak of THC levels in the blood and a longer duration of effect are observed when cannabis is administered orally.40

Hepatic cytochrome P450 (CYP) enzymes control cannabinoid bioavailability. THC is metabolized primarily by CYP2C9, 2C19, and 3A4.40 Drugs that inhibit these enzymes—including proton pump inhibitors, HIV protease inhibitors, macrolides, antimycotics, calcium antagonists, and some antidepressants—can increase the bioavailability of THC.47-49

Conversely, drugs such as phenobarbital, phenytoin, troglitazone, and St. John’s Wort reduce THC bioavailability by increasing the activity of hepatic enzymes.47,49

Canadian Guidelines:  
“Recommending” Medical Cannabis

The government of Canada’s Marihuana for Medical Purposes Regulations (MMPR)50 establishes the legal framework that enables patients to obtain authorization to possess dried marijuana for medical purposes. Under these regulations, physicians have primary responsibility for the decision to authorize patients’ use of dried marijuana for medical purposes. Physicians enable patients to access a legal supply of dried marijuana by completing a medical document that functions like a conventional prescription.

Under such regulations, the patient must consult with a medical doctor or qualified nurse practitioner. A signed medical document is submitted to a licensed commercial producer (of which there are approximately 30 in Canada currently). Alternatively, arrangements may be made for the producer to transfer the drug to the healthcare prescriber from whom the patient can then obtain it. Regulations do impose limits on the total quantity that can be transferred at one time and within a 30-day period.

It should be noted that Health Canada does not currently approve nor regulate medicinal marijuana. Hence, the medical document issued by physicians is distinct from a prescription, but can be considered to be analogous in limited ways. In Quebec, for example, physicians can only provide such a document if it is part of a recognized research project and only for specified conditions. A Supreme Court of Canada decision (R v Smith) dated June 11, 2015, allows licensed producers to sell marijuana for medical purposes in two basic forms: dried and oil. Producers are also required to develop a conversion method among dried marijuana, cannabis oil, and fresh marijuana.

Both the College of Physicians and Surgeons of Ontario and The College of Family Physicians of Canada have set forth their recommendations and practices for medical marijuana use.51,52

Prescribing Considerations

Prescription and recommendation of medical cannabis has typically been nonspecific in Canada. Patients are recommended to a medical cannabis access program, or it is suggested to them that they attempt to sign up as per the advisement of their physician. Increasingly, an understanding of how specific strains of medical cannabis can offer benefit for specific ailments, or not, is appreciated by those recommending the use of medical cannabis. Unfortunately, there is limited knowledge regarding such practices due to a lack of investigation, which prevents physicians from making informed decisions about the use of medical cannabis.

Amount

Some medical cannabis programs have the recommending physician allot a set amount of cannabis to which a patient will have access on a daily or monthly basis. Average patient use of cannabis ranges between 0.68 and 1.5 grams per day, according to medical cannabis programs.29,53 While there are patients who can use up to 10 grams per day of cannabis for medicinal purposes, increasing the amount of cannabis recommended by the physician increases the risk of diversion. The amount recommended should take into account the amount the patient currently uses for self-identified medical reasons as well as the preferred route of administration.

Prescreening precautions and safeguards (similar to those used for opioids) are necessary to prevent diversion. This primarily applies to prescriptions for high THC with smoking/vaporization. As a general rule of thumb—from clinical experience—when the CBD percent amount is 4 times or more higher than the THC percent amount, there are minimal to no psychoactive effects.

Strain Selection and Recommendation

With the limited evidence supporting the use of specific medical cannabis strains for various pain ailments, recommending a strain type to a patient can be difficult. The decision is generally influenced by a number of factors, including financial concerns, potential risk to the patient, and specific goals of the patient (such as to improve sleep or to avoid feeling high).

Typically, recommendations at our clinics are made based on medical history, cannabis use history, and financial barriers. Once all of these factors have been considered, a strain is selected from a range of varieties recommended for medical use. Using the principles of “start low, go slow” titration, individuals with little or no experience, histories of bipolar disorder, strong familial schizophrenia, and/or a history of substance abuse (the latter three conditions may be considered contraindications for use of cannabis) begin their process with medical cannabis on a CBD-dominant strain. Patients with a history of cannabis use and no significant risk factors are initially prescribed a strain with higher THC content and maximal CBD content. If the initial strain does not address the patients’ therapeutic needs, THC content will be increased in a stepwise manner provided that no serious risk factors are present. In the presence of risk factors, the risk-benefit analysis for the patient must be readdressed.

[Editor's Note: Read more on Common Concerns Regarding Cannabis]

Route of Administration

The route of administration is ultimately based on the patients’ needs and capabilities. For example, the patients may have concerns about about the carcinogens present in smoked cannabis being similar to those in tobacco smoke.54

The optimal route of delivering the medicinal content of cannabis,55 both dried and extracted (oils), is by inhalation by vaporization. However, a patient’s ability and need may limit he or she using the vaporizer. For example, certain populations of pain patients, such as those with rheumatoid arthritis and osteoarthritis, may not have the dexterity required to be able to use the grinder to grind the cannabis and load the vaporizer. Patients may also feel uncomfortable with the temperature of the vapor created by the vaporizer. In order to overcome some of these barriers, many patients require extensive training on how to use the vaporizer.

The oral route of administration of medical cannabis is typically preferred for patients with respiratory illnesses.  This method is associated with lower absorption and bioavailability than for inhaled cannabis. It is generally recommended that patients using the oral route require 2.5 times more cannabis than those planning to use a vaporizer.

Oral ingestion typically refers to consumption of cannabis oils or edibles. These are generally produced by infusing a lipophilic substance, like an oil or butter, with cannabis, which is then used in drops or in food. Indeed, a number of recipes have become available online for the use of cannabis oil and butter in food, though some patients dislike the strong flavor.

Another disadvantage associated with the oral consumption of cannabis is a lack of research on its effectiveness and safety. Considering the relatively late onset of effects following oral consumption of cannabis (2-4 hours), patients must be advised to wait a sufficient amount of time before readministering. Despite disadvantages such as dosing and effectiveness, orally administered cannabis is usually well tolerated by patients.

Medical cannabis also can been taken in the form of sublingual tinctures. Tinctures are generally extracted with ethanol, while vinegars and glycerine may also be used. The extract is dropped under the tongue and given a sufficient amount of time to be absorbed via the branches of the lingual artery, including the sublingual and deep lingual arteries.  

This route of administration is associated with a faster absorption rate and an earlier onset of effect following application compared with oral administration.56 Sublingual tinctures may be a desirable option in the future, as they mitigate the dosing and bioavailability issues associated with orally ingested cannabis and eliminate concerns over tolerability with inhaled cannabis. However, it must be noted that there is not enough evidence to support administering cannabis via this route and that patients often complain about the taste.

In Canada, there is the approved sublingual cannabinoid pharmaceutical known as Sativex (THC-CBD mixture with 2.7mg and 2.5mg of each per spray). This was approved in 2005 for multiple sclerosis (MS)-related neuropathic pain or spasticity and for cancer-related pain. In addition to a case series, which was published on its effectiveness for fibromyalgia,37 a recent National Pain Foundation survey has shown that the majority of patients found this superior to FDA-approved medications (Table 1).

Other rarely used routes of administration associated with cannabis include transdermal ointments and balms, ophthalmic drops, and rectal suppositories. Although there may be a therapeutic advantage to using these routes of administration, little research has been conducted to assess this likelihood.

Follow-up Frequency

In order to properly introduce the patient to medical cannabis, frequent follow-up visits must be scheduled until a strain has been chosen that meets the treatment goals of both patient and physician. Initially, an active follow-up schedule may be required to address any changes in the patients’ regimen, such as a need to alter the route of administration. A follow-up schedule will help the patient receive adequate education to be able to continue safely and confidently. After the patient has been stabilized, the focus of the follow-ups should be on monitoring for adverse reactions, including dependence.

Contraindications

Medical cannabis has been associated with several contraindications. There is a lack of research in this area, which is partly due to the illicit nature of cannabis. As a result of this lack of knowledge, medical cannabis recommendations must always carefully consider the patients’ current health status.

Psychosis

As previously mentioned, patients suffering from or at risk of developing schizophrenia or other psychotic ailments must only be recommended the use of medical cannabis under well-monitored conditions. The strains recommended have minimal or no THC content.

Bipolar Disorder

Bipolar disorder is another mental illness for which low-THC content strains are recommended. A recent study has indicated that cannabis use was significantly associated with lower rates of remission of bipolar spectrum patients over a 2-year follow-up period.58 However, studies have shown an association between cannabis misuse and earlier onset of bipolar disorder.59

Cannabis Allergies

Approximately 8% of the general population are allergic to Cannabis Sativa, while the prevalence may be higher amongst individuals who identify as users of cannabis.60 Although some allergic reactions are mild and treatable, avoidance is recommended for patients with cannabis allergies due to the possibility of lethal anaphylaxis. Allergic reactions, such as mild rhinoconjunctivitis symptoms, can be treated with antihistamines, intranasal steroids, and nasal decongestants.61 Another less common treatment available for cannabis allergies is immunotherapy.62-63

Case Studies

Neuropathy and Back Pain

A 55-year-old woman reporting neuropathy and back pain due to the diagnoses of fibromyalgia, Lyme disease, and migraines, occurring for the past 15 years, was referred to our clinic. Her initial baseline recorded pain score in the clinic was 10/10 on a numerical rating scale. The patient also had a history of allodynia and hyperesthesia over the arms, shoulders, and abdomen.

At the time of the initial consult, the patient was taking naltrexone, duloxetine (Cymbalta), rizatriptan (Maxalt), valacyclovir, onabotulinumtoxinA (Botox), thyroxine, and pregabalin (Lyrica). Attempted treatments included physiotherapy, massage, chiropractic, osteopathy, and medications. These interventions helped a little bit, but she could barely stand having even a light massage. She received treatment for migraines and her cervical dystonia with Botox, but she found that it helped only with the nausea associated with the migraines.The patient had not previously used medical cannabis.

The patient was prescribed 1 gram per day for 90 days of a recommended strain of cannabis containing 2.6% to 5.5% THC administered via a vaporizer. At the 90-day follow-up, the patient reported using no external medication other than medical cannabis and her pain score was 6/10 on a numerical rating scale. The perceived benefits from medical cannabis included pain control, improved sleep, and reduced muscle spasms.

Pain Secondary to Multiple Sclerosis

A 47-year-old woman with a 9-year history of multiple sclerosis and fibromyalgia was referred to our clinic for the management of secondary pain. Her initial recorded pain score in the clinic was 8/10 on a numerical rating scale. The patient also reported a history of facial pain, osteoarthritis, and colitis.

At the time of the initial consult, the patient was taking gabapentin, nortriptyline, OxyNeo [an abuse-deterrent formulation of oxycodone that is available in Canada], fentanyl, carbamazepine (Tegretol), baclofen, the proton pump inhibitor pantoprazole magnesium (Tecta), and mirabegron (Myrbetriq). Attempted treatments include physiotherapy, massage, osteopathy, acupuncture, counseling, and medication.

The patient had previously used cannabis for medicinal purposes; her perceived benefits from the cannabis included pain control and poor sleep.

The patient was prescribed 1 gram a day for 60 days of a high CBD strain for daytime and a THC percentage of less than 10%, either via oral administration and/or a vaporizer. At the 60-day follow-up, the patient reported using Tecta, baclofen, Tegretol, fentanyl, OxyNeo, gabapentin, and nortriptyline and was no longer taking Myrbetriq. Her pain score at the 60-day follow-up was 7/10 on a numerical rating scale.

Fibromyalgia—Widespread Neuropathic Pain

A 63-year-old divorced woman (former public health nurse) with fibromyalgia had originally been seen in February 3, 2003. Her diagnoses included a childhood eating disorder, chronic migraine, widespread osteoarthritis (with increased bone scan activity in shoulders, ankles, feet, and spine—T10-12 and L3-5 facet joints), and right carpal tunnel syndrome. When screened for depression, her Beck score was 9/63, indicating that she did not have significant depression.

The patient has undergone extensive medication trails, including tricyclic antidepressants, nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, muscle relaxants, opioids (she is allergic to codeine, meperidine), antimigraine drugs including Topamax, as well as complementary therapies such as acupuncture, massage, pool therapy, naturopathic remedies, and Dr. St Amand’s guaifenesin protocol.  

In December of 2003, she reported a positive response to nabilone starting at 1 mg nightly at bedtime (QHS), titrated up to 2 mg QHS. After 2 months, the patient’s pain improved from 8/10 to 5/10 on the numeric rating scale, and her Fibromyalgia Impact Questionnaire score was lowered from 24.3/100 to 19.3/100. By November 2005, the patient was on the maximum dose of nabilone: 2 mg taken in the morning and 4 mg nightly. However, she developed tolerance to this agent and was tapered off the medication. During the 5 years the patient was on nabilone, she also had tried zopiclone (Imovane), pramipexole (Mirapex), and citalopram (Celexa), which resulted in blurred vision.

In addition, she unsuccessfully tried gabapentin, which made her feel “zonked out” at a higher dose, and onobotulinumtoxin (Botox) injections (November  2004; February 2005; April 2005,  July 2005), with no long-term pain relief. She also had trials of duloxetine (Cymbalta), pregabalin, and sodium oxybate (Xyrem).  Bioidentical and human growth hormone replacement therapies also did not help.  

In 2012, she reported some relief with fluoroscopic-guided facet nerve blocks and subsequently underwent radio-frequency denervation of the lumbar facets with some benefit. Intravenous lidocaine-ketamine infusions every 2 to 3 months also were helpful for neuropathic pain (DN4 score, 7/10) but as the effects wore off, she resumed most of her pain medications.  

On November 10, 2015, she was started on a trial of medical cannabis Indica strain (vaporizer) at a dosage of 1 gram per day (THC 3%-5% + CBD 4%-6%) but felt too “stoned.” The strain of medical cannabis was changed to a Sativa strain with higher CBD (13%-16%) and low THC (0.4%-1%). She reported much improved (80%) pain relief without any psychoactive side effects.

On her follow-up assessment on March 3, 2016, she reported that with the higher CBD strain, she was able to completely wean herself off all of the following medications: gabapentin, zolmitriptan (Zomig), dihydroergotamine (DHE, Migranal), naproxen and esomeprazole (Vimovo), pramipexole (Mirapex), lisdexamfetamine (Vivance), nabilone, Tylenol ES, Advil ES, and Robax Platinum. Her use of magnesium glycinate went from 8, 400 mg tablets per day down to 4 tablets per day.

At her most recent visit, the patient was prescribed high-CBD-containing oils for longer lasting pain relief and was encouraged to increase her exercise (core strengthening and cardio, with appropriate pacing), stress management, and sleep hygiene (same wake and bedtimes, not electronic at bedtime).

Summary

This paper reviews some of the relevant history and current literature on medical cannabis. It highlights the key concerns in the Canadian medical system and provides up-to-date treatment approaches to help clinicians work with their patients in achieving adequate pain control, reduced opioid and other medication use (and their adverse effects), and enhanced quality of life. Further studies are needed with randomized controlled trials and large populations to determine the specific strains and concentrations that work best with a selected subcohort of patients. This is a rapidly emerging field that all pain physicians need to be aware of.

Last updated on: August 4, 2016
Continue Reading:
6 Common Concerns Regarding Medical Marijuana

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