Chronic pain has reached epidemic proportions in the past decade, with an estimated 80 million current chronic pain sufferers in the US.

There has been concomitant exponential growth in the use of prescription opioids for chronic pain. A significant proportion of chronic pain patients are also being treated with benzodiazepines. Much of this increase has been due to more loose prescription guidelines for non-malignant pain, and aggressive pharmaceutical marketing campaigns¹. Even though there is little research to support long term use of opioids for chronic non-malignant pain².

This increased use of addictive and potentially life-threatening medications has been associated with a four-fold increase in the number of deaths from prescription opioids between 1999 and 20112,3. The most recent CDC data estimates that 44 people a day die from prescription opioid overdose. There are over 700,000 opioids-related hospitalizations annually. As many as two thirds of these deaths were in patients prescribed the opioids, who were not using drugs illicitly.   One third of the persons who overdosed on prescriptions opioids were also taking a benzodiazepine. There is also a documented tendency to gradually increase dosage of opioids over time due to tolerance. Also periods of abstinence from opioids, due to access or other issues, may lead to unexpected overdose when the patient resumes the previous tolerated dose³⁴

This epidemic of opioid prescriptions flies in the face of many meta-analyses that have found little evidence that opioids are effective treatment for chronic pain. Another study found almost one million Veterans found that 71% of patients who are started on opioids and maintained on them for at least 90 days, will still be taking opioids three years later⁵. This suggests that medical provider prescribing practices could be a major contributor to iatrogenic opioid dependency and adverse outcomes.Chronic pain patients are commonly denied additional prescriptions for opioids due to failed urine drug testing, most often from THC obtained illicitly.

Even though the patients were often using cannabis for opioid sparing. The net effect is that these opioid dependent patients are suddenly without prescription opioids, and may seek out illicit means of obtaining opioids. Research has shown that over time. Due to access and cost issues, these patients often end up using heroin off the street. This ‘street heroin’ is often cut with Fentanyl® and an even more potent elephant tranquilizer, greatly increasing the chance of fatal unintended overuse. An additional 26 people a day are dying for heroin overdoses⁶⁷. As many as 80% of these deaths were in patients who became addicted to opioids after being prescribed opioids for an injury or surgery⁸.

There has been a public and political outcry to change the situation quickly and effectively. The efforts over the past few years have failed to significantly reverse the above statistics. The addition of medical cannabis, as an adjunct medication may be a significant part of the solution. Cannabis has been shown to have efficacy in opioid sparing, as an alternative analgesic, for mood elevation and to reducing opioid withdrawal and craving.

The CDC has recently released a report⁹ entitled “Prescribing opioids for Chronic Pain,” that recommended “In general, do not prescribe opioids as the first-line treatment for chronic pain.” This guideline excluded palliative or end-of-life care. It also recommended, “avoid concurrent opioid and benzodiazepine use whenever possible.” Benzodiazepines, like opioids, are respiratory depressants. They work synergistically, opioids at receptors in the medulla oblongata and benzodiazepines as CNS depressants. The FDA has recently added a black box warning to address this¹⁰.

In addition a more recent study added a new issue to the prescribed opioid epidemic. It showed dramatic increases in emergency room visits for unintentional overdoses of opioids in young children, and intentional use of family member’s opioids in adolescents¹¹.

Treating Chronic Pain with Medical Cannabis:

Medical cannabis impacts nociception and spasticity in the central nervous system, and inflammatory related pain through peripheral actions. Cannabis can be used topically for acute musculoskeletal injury, but in general most of the benefits of medical cannabis are for chronic pain conditions.

Unfortunately, as it is with using medical cannabis with most conditions, there has been very little high quality research due to the fact that it is a Schedule I drug. However, that has been changing quickly in the past few years and there are some high quality studies and Randomized Clinical Trials (RCTs) to support use of cannabis for certain chronic pain conditions.

One study showed that low-dose (1.29% tetrahydrocannabinol (THC)) vaporized cannabis resulted in 30% reduction in pain in patients already being treated with conventional FDA approved medications. The low-dose was as effective as the medium-dose (3.53% THC)¹². Not all studies have been promising. A study of intractable cancer pain showed no significant pain reduction with CBD only¹³.

Several high quality RCTs are underway to examine the efficacy of cannabinoids with Chronic Regional Pain Syndrome, post-herpetic neuralgia, spinal cord injury and MS.

Centrally-mediated pain, includes several forms of paresthesias, burning and numbness. Also, fibromyalgia is at least partially a centrally-mediated pain condition. Some research suggests that fibromyalgia may represent a cannabinoid deficiency syndrome¹⁴. The American Academy of Neurology reviewed the available literature and “based on the highest quality evidence” considering “safety and effectiveness” determined that CBD alone can help lessen centrally-mediated pain¹⁵.

A survey of 457 Canadian fibromyalgia patients showed that 13% of them were effectively using adjunctive cannabis to control the pain. The Canadian Fibromyalgia Treatment Guideline states that cannabis should be considered for fibromyalgia patients with sleep disturbances¹⁶.

The regions of the brain that have to do with nociception have high levels of CB1 receptors as well as Mu-opioid receptors (MORp). Studies have shown that opioids and cannabinoids work synergistically. A study of tumor pain in mouse models showed that CB1, CB2 agonists had comparable efficacy to morphine¹⁷.

Neuropathic pain is becoming increasingly common as a sequelae of type II diabetes. Unfortunately, there are very few choices for neuropathic pain. Two RCTs of neuropathic pain in HIV patients showed that inhaled cannabis decreased pain by 30% compared to placebo¹⁸. A study of intractable neuropathic pain in patients with MS, brachial plexus injury, limb amputation and spinal cord injury found that CBD was superior to placebo, without side-effects.

Migraines represent a combination myofascial and neuropathic pain. A review of several studies showed that cannabinoid medications can have positive therapeutic effects on pain, nausea and vomiting¹⁹.

Medical cannabis can have significant therapeutic benefit for inflammatory pain and swelling. CB2 receptors are present in large number on mast cells. Stimulation of these receptors results in decreased release of histamine, serotonin and other proinflammatory neurotransmitters²⁰.

Medical Cannabis as an Adjunct Medication:

Medical cannabis can be used as an adjunct medication for opioid sparing. Currently NSAID, antidepressant, anticonvulsant, and topical analgesic preparations are being used in conjunction with opioids, to reduce the amount of opioid necessary for adequate pain control. Opioid sparing, implies, that a lesser dose of opioid can be used to get the same effect, through synergistic effects of non-opioid medications.

Unlike the other options for opioid sparing, medical cannabis also has positive impact on mood, improving anxiety, usually treated with benzodiazepines, that is commonly associated with chronic pain syndromes. In addition, medical grade cannabis, with balanced ratios of CBD to THC, has a far superior adverse effect profile compared to other medications. Also, cannabis positively impacts inflammation, and spasm which often accompany chronic pain.

Decreasing the dose of opioids, via opioid sparing, leads to fewer accidental overdoses, and less adverse effects such as intractable constipation. A recently released analysis of the literature from the National Cannabis Industry Association (NCIA) discussed some promising observational and population-based findings supporting the use of cannabis as an adjunct to opioids and for tapering off opioids²¹.

The primary objective of adding cannabinoid medication to chronic opioid therapy is to reduce morbidity and mortality associated with opioids, and improve function. This should be done, while also preventing development of significant adverse effects such as euphoria, psychosis, or cannabis dependency. The initial goal of opioid sparing, is to use cannabinoids safely to decrease the frequency of use and dose of fast acting opioids for breakthrough pain. The next goal is to gradually and safely reduce the dose and frequency of both slow and fast acting opioids for the baseline pain.

The goal of the initial phase of opioid sparing is to have the opioid patient learn to appreciate the ability to obtain symptom relief without any opioid, using the adjuncts of cannabis and other non-opioid medications initially. The patient can then take part or all the usual opioid dose if necessary. Over time, studies have shown, that a significant percentage of patients will spontaneously discontinue opioids altogether in lieu of cannabis and other non-opioid medications²².

Cannabis, can also be used to discontinue opioids for pain control. Cannabis has innate analgesic and anxiolytic effects as well as beneficial effects on opioid craving, and on the severity of opioid withdrawal-related nausea and muscle aches.

A study of people using cannabis to taper off opioids showed that the common side-effects of chronic opioid use: constipation, depression, and nausea were significantly reduced with concomitant use of cannabis²³.

Therapeutic Effects of Cannabis:

Cannabis has therapeutic effects on pain via the Endocannabinoid System (eCS). See Appendix I to read more about the eCS. Cannabis works via the CB1 and CB2 receptors, and by modulating the effects of opioids at MOPr. THC is a partial agonist of both CB1 and CB2 receptors and has beneficial effects on nociceptive pain, and neuropathic pain via CB1 receptors, and inflammation, spasticity and myofascial pain via CB2 receptor agonism²⁴.

There are over a hundred phytocannabinoids in cannabis sativa. Only, THC and cannabidiol (CBD) have been studied extensively. THC has been shown to have 20 times the anti-inflammatory potency of aspirin, and twice that of hydrocortisone in neuropathic pain. However, unlike NSAIDs and aspirin, THC does not demonstrate cyclooxygenase (COX) inhibition. COX-1 and COX-2 inhibition are associated with the gastrointestinal and cardiovascular adverse effects associated with NSAIDs²⁵.

CBD, has minimal agonism on eCS receptors, but increases the amount of the naturally occurring endocannabinoid, anandamide
(AEA). CBD inhibits fatty acid amidohydrolase (FAAH), which is the hydrolytic enzyme of AEA. CBD primarily impacts CB2 receptors which are present on immune system cells in the brain and body, resulting in anti-inflammatory effects.

Medical cannabis is not the only way to use the eCS to relieve pain. The terpene, beta-caryophyllene, found in large quantities in many strains of cannabis sativa, as well as many other food spices, is a selective agonist of CB2, positively modulating inflammation, neuropathic pain, anxiety and spasticity.

Cannabis and Mu-Opioids Receptors:

Mu-opioids receptors (MOPr) are also G protein-coupled receptors. They are the site of action of innate opioids and of opioid medications. Opioid medications reduce pain by binding to and stimulating mu-opioids receptors in the central nervous system, leading to a decreased perception of pain via inhibition of ascending pain pathways that start in the spinal cord.
MOPr are heavily expressed on respiratory neurons in the brainstem.

Potent mu-opioid agonists therefore, can cause respiratory depression, the most common cause of opioid overdose death. There are essentially no cannabinoid receptors in the brainstem, which is the primary reason that no overdose deaths have ever been associated with cannabis use.

Both THC and CBD are allosteric modulators of mu-opioids receptors. This results in indirect amplification of the effects of opioids at the mu-opioids binding site. This effect is associated with observed synergistic effects of cannabis and opioid medications.

Cannabinoid Pharmaceuticals:

Dronabinol, which goes under the proprietary name of Marinol®, is a synthetic analogue of THC. It is different from plant-derived THC and is a full agonist of cannabinoid receptors, unlike plant-derived THC which is a partial agonist. Dronabinol has been studied as a mono-molecule drug, and not as part of a whole plant extract. Whole plant extracts have been shown to have reduced adverse effects due to the antagonistic effects of CBD on THC adverse effects, and through the ‘Entourage Effect’ of CBD, minor cannabinoids, and terpenes.

Dronabinol, has been FDA approved since 1985. It was originally placed in Schedule II of the Controlled Substances Act. But, based on the clinical experience and lack of expected issues with adverse effects and only mild to moderate physical dependency syndromes, it was rescheduled to Schedule III in 1999. It has not been reviewed by the FDA for use in pain, but it has been shown to increase analgesia among patients taking opioids for chronic non-malignant pain²⁶.

Nabiximols, which goes under the proprietary name of Sativex® is a whole plant extract in phase III trials in the US. It was approved in Canada in 2005 for central neuropathic pain and intractable spasticity in multiple sclerosis, and in Canada 2007 for intractable cancer pain. It is made up of extracts from two strains of cannabis sativa that result in a 1:1 ratio of THC to CBD. Numerous randomized clinical trials (RCTs) have demonstrated safety and efficacy of Sativex® in central and peripheral neuropathic pain, rheumatoid arthritis and cancer pain. Phase III trials of Sativex® showed a statistically significant 30% or better improvement in their pain score compared with placebo. There was an average of 43% improvement with Sativex® . These studies used an average of 22-32mg/day of THC and 20-30mg/day of CBD in an oromucosal spray²⁷.

Phase III trials of Sativex® showed a 30% mean improvement in diabetic neuropathic pain, and one third of the patients achieved 50% improvement. But the placebo group also had an unexpectedly large response and the study did not reach statistical significance.

Similar results would be expected from extracts available at the thousands of medical cannabis dispensaries around the country. While Sativex® is not FDA approved yet, these other extracts are currently available. The fact is, Sativex® is just another version of a 1:1 CBD to THC whole plant extract of cannabis sativa. Similar whole plant extracts of 1:1 CBD to THC, that are of high quality, laboratory tested, and contaminant free are available in dozens of states with medical cannabis laws.

These extracts sell at a fraction of the cost of Sativex®. In addition, there are a variety of ratios, 2:1, 18:1 CBD to THC extracts in a various dosages available, unlike Sativex® which only comes in one formulation²⁸. RCTs of Sativex® have shown minimal issues with drug-drug interactions or impact on cytochrome P450 enzymes, when used as an adjunct with opioid medications.

Studies have shown that cannabis dependence syndromes are a sequelae of long term, frequent use of high doses of cannabis with high THC, low CBD ratios. This is the type of cannabis most often associated with recreational use. CBD alone is not associated with euphoria, psychosis or dependency syndromes. The 1:1 CBD to THC ratio in Sativex® and micro-doses of THC compared to recreational doses are probably the reason that no withdrawal symptoms or dependency syndromes have been associated with up to one year use of Sativex®. Similarly, cannabis that is higher in CBD than THC, either in extracts, or smoked or vaporized would not be expected to be associated with dependency syndromes, or the adverse effects associated with high THC to CBD ratio cannabis.

Other Opioid Sparing Medications:

Acetaminophen, is one of the most commonly used over-the-counter pain medications. Unlike NSAIDs and aspirin, which are COX inhibitors, acetaminophen has no gastrointestinal adverse effects or untoward cardiorenal effects²⁹. It is a common opioid sparing ingredient combined with opioids in several common prescription medications. The previous 500mg dose of acetaminophen in these combination tablets, was reduced to 325mg in 2014 to reduce the chance of hepatotoxicity from taking many tablets a day.

Safety of Medical Cannabis:

Medical cannabis has been used in Western medicine for almost two hundred years for a wide variety of conditions. At the turn of the 20th century there were over 2000 ‘patent’ medications containing cannabis sativa extract, and it was the second most common ingredient in prescription medications.

Cannabinoid medications are in general much safer, with fewer adverse-effects, and a much broader therapeutic window than opioids or NSAIDs. In addition, with medical doses of CBD/THC balanced cannabis the occurrence of temporary psychosis, euphoria, dependency syndromes, or withdrawal are rare, self-limiting and of short duration³⁰.

The concept of cannabis as a “gateway drug” has been debunked by the National Academies of Medicine in 199930. To the contrary, studies from Holland suggest that legal cannabis use actually decreased the likelihood of trying cocaine and amphetamines³¹.
A recent one year long prospective cohort study from Canada³² evaluated the safety of herbal cannabis use for chronic non-cancer pain in 215 patients. The study participants were using up to very large amounts of 312mg THC a day in inhaled or edible cannabis. There were no increases in serious adverse effects. However, there were increased rates of mild to moderate adverse effects. The authors concluded, “when used by patients with experience of cannabis use as part of a monitored treatment program over one year, appears to have a reasonable safety profile.”

Although there are no fatalities associated with overdosing on cannabis, problems with decreased coordination have been associated with numerous cases of “death by accident.”³³

Chronic Pain and Medical Cannabis Use:

Among the over 1 ½ million patients in the US who use medical cannabis legally, chronic pain is by far the most common condition for which medical cannabis is recommended. Most studies suggest that 85-94% of medical cannabis patients are using it for ‘pain’8. These figures may be blurred by the fact that “chronic pain” is a subjective condition, and easier to prove than other Qualifying Conditions in states with medical cannabis laws. Therefore, people may be feigning a chronic pain condition, solely to bypass prohibition against the recreational use of cannabis. However, this same phenomenon occurs regularly with opioid and benzodiazepine prescriptions.

A study of Canadian pain clinics showed that 10-15% of the patients were using medical cannabis as well as other pain medications. Two large-scale population-based studies in Australia and the UK showed that about one third of people using cannabis for medical purposes were using it for arthritis pain, often without medical provider supervision. Eighty percent of medical cannabis users reported substituting cannabis for prescribed medications, especially among patients with pain-related conditions.

The University of California Center for Medicinal Cannabis Research (CMCR), released a report in 2010³⁴. It reviewed the findings of a decade of randomized, double-blind, placebo-controlled clinical trials of inhaled cannabis. It concluded that medical cannabis should be a “first line treatment” for chronic neuropathic pain. A meta-analysis of 79 studies from 2015 found a 30 percent reduction of pain with use of cannabinoids compared to placebos. The concluded “We now have reasonable evidence that cannabis is a promising treatment in selected pain syndromes.”

A 2016 University of Michigan study was published of 244 patients using medical cannabis as an adjunct to control chronic pain. They found 64 percent reduction in the use of opioids. They also noted fewer side-effects from opioids and 45 percent improvement of quality of life since adding medical cannabis to their treatment. Cannabis has also been shown to decrease development of tolerance to opioids or severity of withdrawal³⁵³⁶.

In 2010, a study by Dr. Donald Abrams examined the use of inhaled cannabis vapor, three times a day for five days, in 24 pain patients using either morphine or oxycodone³⁷. The findings included a 33% reduction in pain with in the cannabis and morphine patients, and a drop in pain from 44% to 21% by day five in the cannabis and oxycodone patients.

A systematic review and meta-analysis of cannabinoids for medical use completed in 2015 arrived at the conclusion that ‘there was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic neuropathic or cancer pain; using smoked THC or nabiximols’. These findings also suggest that lower total doses of opioids can be used when the patient is using cannabis, thereby further reducing the chance of adverse effects and overdoses of opioids. “There is a lot of data suggesting if you pair high-potency cannabinoids with opioids you get an enhanced effect.”

A small study of patients using long acting opioids, showed that concomitant use of vaporized cannabis was associated with additional decreases in measured pain levels. Another study of CBD used in combination with morphine in mice showed synergistic effects on nociceptive pain³⁸.

A study of 24 hospitalized patients using morphine or oxycodone for chronic pain showed that three daily doses of vaporized cannabis, measurably improved pain control by 33-44%. The euphoria associated with the vaporized cannabis became less noticeable within three to five days, but the anti-nociceptive effects persisted.

A survey of 542 patients took opioids and cannabis together. 39% reduced their opioid dosage and 39% stopped opioids altogether³⁹.

Observations from States with Medical Cannabis Laws:

We can learn much from the epidemiologic data that has come out of the states with medical cannabis laws.

A well conducted survey during the period 1999-2010 showed a 25% reduction in the rate of lethal opioid overdose in those states that enacted medical cannabis laws. The effect strengthened over time from 1999 to 2010, to 34% reduction by 2017.

Another study found that states with medical cannabis had 28-35% reduction in opioid addiction admissions, and 16-31% reduction in overdose deaths⁴⁰.

A recently published analysis of Medicare Part D drug sales from 2010-2013 showed markedly lower prescribing of “pain killer” and “anxiety” medications in the 17 states that have medical cannabis laws. There were 1826 fewer doses of pain medications, and 562 fewer doses of anxiety medications per medical provider in those states⁴¹. An unpublished draft of a follow up paper on Medicaid drug sales showed even stronger findings.

Using Medical Cannabis in Clinical Practice:

The biggest problem with getting medical professionals to add medical cannabis to the list of drugs for chronic pain, is that it that the ‘medication’ is either plant material, plant tinctures or extracts, or edibles. Most clinicians have very little experience with recommending or dosing a medication in this format. In addition, the quality, consistency, potency and presence of contaminants is highly variable with these mostly unregulated products⁴². The medication is obtained at a dispensary and not a qualified pharmacy and the health insurance does not pay for the medication, which averages $100-200 a month or more.

There are also the health concerns associated with smoking plant material. GW Pharmaceuticals has attempted to address all of these issues, producing a whole plant medication, that meets the stringent requirements of FDA approval. Their pharmaceuticals, Sativex® and Epidolex®, will be available in retail pharmacies, not dispensaries. However, previous experience with Sativex®, that is available in over 20 countries by prescription for over 6 years. Research suggests that the high cost of the product has limited access⁴³.

Cannabis sativa is a species of plant that has two medically active sub-species, cannabis sativa sativa, and cannabis sativa indica. The sativa strains historically have been associated with high levels of CBD and low levels of THC and the indica strains high levels of THC and low levels of CBD.

Over the past few decades there has been significant cross-breeding and hybridization, resulting a hundreds of new strains often with names associated with the euphoric or relaxing effects.

Medical providers do not need to be aware of strains of cannabis. The important therapeutic aspects of cannabis, at this time, are the amount each of THC and CBD. For whole plant material the amount is provided as a percent, for example if cannabis flower is 12% THC and 5% CBD. This means that the 12% of dry weight of the plant material is THC oil, and 5% is CBD oil. It also means that this cannabis has a CBD:THC ratio of 12:5 (or about 2:1). This information is provided by the dispensary, and should be documented in a laboratory test result from an independent, state or ISO certified laboratory. Appendix II has a discussion of how to calculate doses of smoked cannabis.

For vaping fluids, extracts, tinctures, edibles and dermal applications, the label provides the number of milligrams of THC, CBD, some other cannabinoids and often terpenes, per milliliter or per serving. Many of these ingested manufactured products are made by small manufacturers and may have issues with quality, consistency, and contamination with pesticides, molds, and heavy metals. A recent study of Colorado dispensaries found 85% had inaccurate doses, 23% had more and 60% had less THC than stated on the label46. Recently enacted state laws should improve this situation. A good dispensary will have the labels confirmed by independent, high quality laboratories.

Most clinicians are not familiar with helping patients calculate the dose of their medication. Most good dispensaries will have staff members trained on how to teach the patient to calculate the correct dose.

How to Use Medical Cannabis for Opioid Sparing:

The goal of opioid sparing, is to decrease the amount of opioid being used, while maintaining the same level of pain control. The motivation for opioid sparing includes reducing potential for life-threatening overdoses, decreasing the development of tolerance and escalation of opioid dosing and reducing serious adverse effects associated with long term use of high dose opioids.

With these goals in mind, clinicians can add medical cannabis to the treatment regimen. The therapeutic plan includes titrating a dose of cannabis prior to each opioid dose. When a fast acting opioid is used, the patient will use fast acting smoked, vaporized cannabis, or a tincture sublingually. When a slow release opioid is used, the patient will use ingested cannabis, such as an edible, swallowed tincture or extract, as these are slow release medications.

The educated patient will have been taught to “start low, and go slow.” For a vaporized or smoked cannabis, the patient will take the recommended dose, then wait 20 minutes. The cannabis will reach peak plasma concentrations in the blood in 9-23 minutes. If pain control is not sufficient, the patient will then take a second dose, again waiting 20 minutes to decide to either try a third dose of cannabis, before taking the fast acting opioid. If the patient has measurable improvement in pain levels from the cannabis alone, but not sufficient, then he may try taking half of the usual dose of the fast acting opioid medication. This is due to the expected synergistic effects of the cannabinoids at the MORp.

The process is similar for ingested, or slow release cannabis medications. These are used to spare the use of slow release opioids. The patient will take the dose recommended by the medical provider. The patient will need to wait 60 minutes, because of the slow release and first-pass effect. The mean peak plasma concentration time of 60-120 minutes and therapeutic efficacy can last up to 6 hours. The metabolite of THC, 11-OH-THC, is 40% more potent than THC, therefore, no second ingested dose is taken.

If after an hour there is not sufficient pain relief, then the patient can decide to take either half the usual dose of slow release opiate, or the full dose. If there was insufficient pain control with that dose of ingested cannabis, after 4-5 days at this dose, the patient can increase the dose by 50%. Again, evaluate this dose for 4-5 days, before considering increasing the dose. This is part of the slow titration of dosing with which most patients will quickly become comfortable.

THC is usually limited to 10mg per dose, up to 4 doses a day. More than 10mg of THC per dose is associated with getting euphoria or temporary adverse effects. In addition, use of high levels of THC can result in down-regulation of cannabinoid receptors and promote tolerance to the cannabis medication.

Once the patient is taking 10mg of THC per dose, then only the amount of CBD per dose will increase. A typical scenario is that the patient is taking 10mg each of 1:1 CBD to THC in an ingested cannabis medication, in the morning and at bedtime for chronic pain. If this is not giving sufficient pain control throughout the day, the patient can increase the frequency up to four times a day. Then increase the amount of CBD in the product, for example increase to 25mg CBD and 10mg THC per dose.
Another choice is to add a low THC/high CBD vaporizer used regularly throughout the day. CBD is very safe, and used alone has measurable impact on pain and inflammation. Adding over a 50mg (20 vaporized inhalations) of extra CBD a day via this route is not uncommon.

Once pain reduction has been established with the use of cannabis, the use of opioid pain medications can gradually be reduced, keeping in mind the potential for opioid withdrawal and the need for an established protocol for weaning.
Start at a low dose of cannabis, where the benefit for pain relief occurs, and where the euphoric or dysphoric effects of cannabis are less likely to occur. Start low and titrate up slowly. For chronic pain is 2.5mg of THC and CBD (1:1 ratio) at morning and bedtime is a recommended starting dose. If the dose is ingested via an edible, or swallowed tincture, it will take about 60 minutes to start having effects, but should have pain-relieving effects for up to six hours.

Vaporized or inhaled cannabis can be used for quick onset to treat breakthrough pain. Usually two inhalations (4-5mg) of smoked of vaporized cannabis is taken, and wait at least 20 minutes to determine if additional inhalations are appropriate.

Because of the desire to impact the nociceptive centers in the CNS, neuropathic pain and inflammatory component of the pain, both CBD and THC are recommended. In order to reduce the chance of euphoria, and other adverse effects associated with THC alone, it is recommended that a ratio of CBD:THC of 1:1 be used initially. This ratio works for most patients.

There is no comparison chart of THC/CBD to Morphine Equivalent Dose (MED). Because of the previously discussed issues with the potency, and consistency of cannabis doses, it is important to start well below the expected therapeutic dose and gradually titrating the dose upwards. The dose can be titrated up every 4-5 days until measurable reductions in pain are noted. Usually the dose is increased in 2.5mg increments, to 5mg, 7.5mg, then 10mg.

Cannabinoid medications have an inverse U-shaped dose-response curve. Because of this it the initial doses may have no effect. Once a dose is reached with therapeutic effects, the dose should be titrated up more slowly until there is a maximum effect. As the dose increases past the maximum therapeutic effect, tolerance may develop due to down-regulation of “flooded” cannabinoid receptors.

Doses of THC above 10mg in 1:1 cannabis can be associated with euphoria. Higher doses can result in temporary psychosis, anxiety, dysphoria, and agitation, especially if there is only a low ratio of CBD to counteract these adverse effects of THC.

Tapering Off or Discontinuing Chronic Opioids:

Patients have historically been tapered off opioid medications at a certain predetermined rate that ranges from 10% to 50% per month. The medical provider, based on training, experience and recent research should discuss the taper rate, and expected quit date, usually from 2 to 10 months in the future. The medical provider will need to re-establish the Pain Contract with the patient, with the addition of cannabis, and educate the patient on the proper use, dosing, safe storage, and awareness of adverse effects. The medical provider usually monitors the progress of the tapering with regular visits and review of a Pain diary.

Discontinuing Opioids:

Totally stopping opioids is another potential goal for medical cannabis. In this scenario, the goal is to replace opioids with medical cannabis. Prior to attempting this goal, the patient should have satisfactorily gained the skills, experience and education necessary to use medical cannabis for opioid sparing purposes. After they have been able to halt escalation of opioid doses, and often reduce opioid doses, they may be interested in entirely substituting opioids and/or benzodiazepines with medical cannabis. Anecdotally, many patient who use medical cannabis for opioid sparing, may attempt to taper off opioids and benzodiazepines on their own, because of the pleasant mood elevation, relief from constipation, and reduction of several opioid adverse-effects. However, any tapering needs to be done in conjunction with the treating clinician to avoid withdrawal or other adverse sequelae.
Unlike most medications, the patient will often feel comfortable adjusting the dosing of the cannabis medication, this patient centered titration is unique to medical cannabis, but in general is a very safe and effective way to reduce dangerous opioids and benzodiazepines and obtain long term consistent pain and associated symptom relief.

Appendix I: Endocannabinoid System

The Endocannabinoid System (eCS) has been present in all vertebrate life for the past 600 million years. Receptors for the eCS are the most common neurotransmitter receptor in the brain and the second most common in the body. The eCS is the main fat soluble neurotransmitter in the body. Unlike dopamine, GABA, acetylcholine, serotonin, which are water soluble neurotransmitters. The eCS is responsible for homeostasis of a wide variety of other system in the brain and body, in general the eCS is responsible for retrograde slowing down a system when it gets over stimulated from dozens of other neurotransmitters. The eCS works on following broad areas of bodily functioning including, nociception centrally and peripherally, inflammation, reward behavior and spasticity. In the brain the eCS reduces anxiety through effects in the limbic and paralimbic brain areas, which are rich in endocannabinoid receptors.

The eCS has at least two receptors (CB1, and CB2), two ligands, anandamide(AEA) and 2-Arachidonoylglycerol (2-AG) and two enzymes that breakdown the ligands intracellularly, FAAH and monoacylglycerol lipase (MAGL).

THC was discovered by Dr. Rafael Mechoulam at the University of Tel Aviv in the 1964. The eCS with its associated ligands was not discovered until 1990. Significant new aspects of the eCS continue to be discovered.

The eCS produces the ligands, AEA and 2-AG on-demand in the postsynaptic membrane. This occurs in response to excess of other neurotransmitter stimuli. The ligands are produced in microseconds and released into the synaptic cleft to attach to pre-synaptic endocannabinoid receptors. This results in shutting down calcium channels, and a decrease in the release of other neurotransmitters.

The ligand is then transported inside the cell via specialized proteins, and degraded by FAAH or MAGL. So these naturally occurring ligands have very short-lived effects.

When plant-based cannabinoids, phytocannabinoids, such as THC and CBD are released into the bloodstream via inhalation, ingestion or dermal application, they are rapidly distributed throughout the body and transported across the blood-brain barrier to attach to CB1 and CB2 receptors.

The affinity and number of cannabinoid receptors varies considerably in different brain centers and organ systems. It is for this reason that small doses of cannabinoids can have therapeutic effects, without the adverse effects of euphoria, anxiety or psychosis. The correct dosing and ratio of CBD:THC are vital to maximizing therapeutic effects and minimizing adverse effects.

Phytocannabinoids work therapeutically by mimicking the effects of the naturally occurring endocannabinoids. Since they are mimicking fat soluble neurotransmitters, they work very similarly to the way gabapentin mimics GABA. In fact, there are many similarities to gabapentin, the therapeutic window is very wide and adverse effects are short-lived and non-fatal.
Unlike the naturally occurring ligands, the phytocannabinoids are not metabolized by FAAH and MAGL. In fact, part of the efficacy of the phytocannabinoids may be due to their competing with intracellular fatty acid transport proteins (FATP) so that naturally occurring ligands are metabolized more slowly and have a more longer lasting effect.
The phytocannabinoids are only partial agonists of the endocannabinoid receptors, but have a much longer half-life than the rapidly disappearing endocannabinoids.

Up and Down Regulation and Tolerance:
CB1 and CB2 are GPR55 membrane receptors. The number of cannabinoid receptors on cell membranes varies considerably in different areas of the brain. The numbers of receptors changes in response to up- and down-regulation. The CB1 receptors are found mostly on neurons in certain brain centers and the CNS. But are also present in the lung, liver, skin and several other areas of the body.

The CB2 receptors are found predominantly on immune system cells in the brain and body, as well as reproductive cells and in the liver and spleen. CB2 receptors are temporarily up-regulated at sites of trauma, where they are usually not present, leading to increased sensitivity to the anti-inflammatory effects of CBD.

If a receptor is overstimulated, or ‘flooded’ with ligands, as can occur with too much phytocannabinoid medication, this results in a down-regulation of the receptors, and can lead to the development of tolerance.

Appendix II: Calculating the Dose of Inhaled Cannabis

It is important that the medical provider understand the basics of dosing In general, when it comes to dosing medical cannabis the main concern is getting approximately the correct dose of THC. All of the adverse effects, euphoria and issues with dependency are associated with THC. CBD on the contrary, is non-euphoric, is not associated with dependency and has only some mild calming (anxiolytic) effects at the doses recommended for pain management.

The therapeutic window of CBD is very large up to 100’s milligrams per dose. inhaled medical cannabis. If plant material is 18% CBD and 0.5% THC, which is the cannabis used for childhood epilepsy, then 18% of the dried plant material is CBD oil. The average amount of plant material in an average ‘joint’ has been estimated as 300-500mg. Research for the micro-dose inhaler to provide tiny doses of cannabinoids for medical use, calculated the average ‘joint’ to be 400mg of plant material in a 1 ¼ rolling paper. Since 18% of the material is CBD oil, then 18% of 400 (0.18 x 400) equals 72 milligrams of CBD.

Since half of the oils are incinerated by the process of combustion, a patient smoking an entire joint would be expected to get 36 milligram of CBD. When cannabis oil or extract is vaporized, as opposed to being smoked, there is no combustion so the patient gets mostly vaporized oil. The dose will vary considerably by the brand, and concentration of the medication. The package insert for these products should provide information on the available dose of THC and CBD in the product.

As it is with edibles, the labels on these locally manufactured extracts, and tinctures can be quite inaccurate. The dispensary should also have independent laboratory analysis of the products.

Appendix III: Chronic Cannabis Users

Patients who have already been chronically using cannabis, often for recreational purposes, will need to have their cannabinoid receptors reprogrammed prior to starting treatment.

The goal is to up-regulate the number of cannabinoid receptors in these ‘veteran’ patients, because they have been down-regulated by frequent, high doses of cannabinoids. Patients with prior regular use of cannabis, should be advised to discontinue all cannabis for three days. Then start at a low dose of 1.25mg of THC and CBD for three days. Then the patient can increase to the full recommended dose, before evaluating efficacy of the dose and medication. This period of time with less cannabinoid stimulation results in up-regulation of cannabinoid receptors and improved response to cannabinoid doses.

References:

1. Morbidity and Mortality Weekly Report (MMWR), March 2016, CDC Guidelines for Prescribing Opioids for Chronic Pain – United States, 2016.
2. Injury Prevention and Control: Opioids Overdose. Centers for Disease Control and Prevention. Oct 3, 2016
3. Rudd RA, Aleshire N, Zibbell JE, et al. Increases in Drug and Opioids Overdose Deaths – United States, 2000-2014. MMWR 64(50);1378-82. 2016.
4. Chen LH, Hedegaard H, Warner M. Drug-poisoning death involving opioids analgesic: United States. 1999-2011. NCHS data brief, no 166, Hyattsville, MD: National Center for Health Statistics. 2014.
5. American Academy of Pain Medicine (AAPM) 30th Annual Meeting. Abstract
6. Chen LH, Hedegaard H, Warner M. Quickstat: Rates of death from drug poisoning and drug poisoning involving opioids analgesics- Units States, 1999-2013. MMWR 64(01):32. 2015.
7. Chen LH, Hedegaard H, Warner M. Drug-poisoning death involving opioids analgesic: United States. 1999-2011. NCHS data brief, no 166, Hyattsville, MD: National Center for Health Statistics. 2014.
8. Bachhuber MA, Saloner B, Cunningham CO, et al. Medical cannabis laws and opioids analgesic overdose mortality in the United States, 1999-2010. JAMA Intern Med 2014 Oct;174(10) :1668-1673

9. FDA Drug Safety Communication: FDA warns about serious risks and death when combining opioids pain or cough medicines with benzodiazepines; requires its strongest warning. http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm
10. Tadros A, Layman SM, Davis SM, et al. Emergency Department Visits by Pediatric Patients for poisoning by prescription opioids. Am J Drug Alcohol-Abuse. 2016 Sep;42(5):550-555.
11. Wilsey B, et al. Low Dose Vaporized Cannabis Significantly Improves Neuropathic Pain. J. Pain, 2013 Feb 14(2): 136-148

12. Johnson R, et al. Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patient with intractable cancer-related pain
13. Russo, E.B. (2008, February). Cannabinoids in the management of difficult to treat pain. Therapeutics and Clinical Risk Management, 4(1), 245-259.
14. www.aan.com/Guidelines/home/GetGuidelineContent/650
15. Ste.-Marie PA, et al. Herbal cannabis use in patients labels as fibromyalgia is associated with negative psychosocial parameters. Arthritis Care Res 2012 June 21.
16. Klauke AL, Racz I, Pradier B, et al. The cannabinoid CB2 receptor-selective phytocannabinoid beta-caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic pain. EurNeuropsychopharmacol. 2014
Apr;24(4):608-20

17. Abrams DI, et al. Cannabis in painful HIV-associated sensory neuropathy – A randomized placebo-controlled trial. Neurology 2007 Feb;68(7):515-521
18. Baron, E.P. (2015, June). Comprehensive Review of Medicinal Marijuana, Cannabinoids, and Therapeutic Implications in Medicine and Headache: What a Long Strange Trip It’s Been. Headache, 55(6), 885-916.

19. Stott CG, Guy GW, Wright S, et al. The effects of cannabis extracts Tetranabinex and Nabidolex on human cyclooxygenase (COX) activity. International Cannabinoid Research Society. 2005 Jun Clearwater, FL.
20. Cannabis: A Promising Option for the Opioids Crisis. NCIA, October 2016.
21. Kay L, Holtzman S. Substituting marijuana for prescription drugs, alcohol and other substances among medical marijuana patients: The impact of contextual factors. 2015 Drug and Alcohol Review

22. Haroutounian S, et al. The Effect of Medicinal Cannabis on Pain and Quality-of-Life Outcomes in Chronic Pain: A Prospective Open-Label Study. Clin J Pain. 2016 Dec;32(12):1036-1
23. Ruhaak LR, et al. Evaluation of the cyclooxygenase inhibiting effects of six major cannabinoids isolated form Cannabis sativa. Biol Pharm Bull.
2011;34(5):774-8.

24. Narang S, Gibson D, Wasan AD, et al. Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioids therapy. J Pain 2008
Mar;9(3):254-264

25. Positive results from clinical study of Sativex in cancer pain published in peer review journal, Nov 2009.
26. Results of Sativex Phase III Neuropathic Pain Trials Demonstrate Benefits for HIgh Need Treatment-Resistant Patients, Jan 2007.

27. Whiting PF, et al. Cannabinoid for Medical Use, A Systematic Review and Meta-analysis.JAMA.2015:313(24):2456-2473.

28. Deer TR, Leong S, Gordin V. Treatment of Chronic Pain by Medical Approaches: the American Academy of Pain Medicine, textbook on patient management. 2015 p. 189-190
29. Schultz S, DeSilva M, Gu TT, et ta. Effects of the Analgesic Acetaminophen (Paracetamol) and its para-Aminophenol Metabolite on Viability of Mouse-Cultured Cortical Neurons. Basic and Clin Pharm and Toxicology;110:141-144

30. Bertolini A, Ferrari A, Ottani A, et al. Paracetamol: new vistas of an old drug. 2006 Fall-Winter;12(3-4):250-75

31. Joy J. Marijuana and Medicine: Assessing the Science Base. The National Academies Press 1999.

32. MacCoun RJ. What can we learn from the Dutch Cannabis Coffeeshop experience? Addiction 106(11) 1899-1910 (2011)

33. Ware MA, Wang T, Shapiro S, et al. Cannabis for the Management of Pain: Assessment of the Safety Study (COMPASS), JH Pain 2015 Dec;16(12):1233-42

34. Prevalence of Marijuana Involvement in Fatal Crashes: Washington,
2010-2014. American Automobile Association report May 2016.
35. Grant I, et al. Report to the legislature of the state of California presenting findings pursuant to SB847 which created the CMCR and provided state funding. 2010.

36. Boehnke KF, Litinas E, Clauw DJ. Medical Cannabis Use is Associated with Decreased Opioid Medication Use in a Retrospective Cross-Sectional Survey of Patient with Chronic Pain. J Pain. 2016 Jun;17(6):739-744

37. Lucas P. Cannabis as an adjunct to or substitute for opioids in the treatment of chronic pain. J Psychoactive Drugs. 2012 Apr-Jun;44(2):125-33
38. Abrams D, et al. Cannabinoid-Opioids Interaction in Chronic Pain. Clinical Pharmacology and Therapeutics 90(6) 844-851
39. Neelakantan H, Tallarida RJ, Reichenbach ZW, Tuma RF, Ward SJ, Walker EA. Distinct interactions of cannabidiol and morphine in three nociceptive behavioral models in mice. Behav Pharmacol. 2014 Dec 5.

40. The Cannabis and Opioids Survey. Healer.com Oct 4, 245.

41. Brittany B, et al. Opioid substitution and antagonist therapy trials exclude the common addiction patient: a systematic review and analysis of eligibility criteria. Trial. 2015;16:475

42. Bradford and Bradford, Health Affairs Jul 2016.

43. Ryan Vandrey, PhD, et al Cannabinoid Dose and Label Accuracy in Edible Medical Cannabis Products. JAMA. 2015;313(24):2491-2493