Cover Story

Physicians explore cannabinoids as pain management solution

Cannabinoids may complement rehabilitation, physical therapy, joint or spinal injections

In 2018, WHO reported musculoskeletal conditions accounted for a greater proportion of persistent pain, with more than 150 diagnoses that affect the locomotor system. Although there are approved medications to treat musculoskeletal pain, sources who spoke with Orthopedics Today said these medications may not work or be suitable for all patients, especially for long term use, depending on their medical status.

“Even though [medications for musculoskeletal pain] can be effective, they are not effective for [some] people and they are not as safe as we would be led to believe,” Jerome A. Schofferman, MD, board certified in internal medicine and pain medicine, told Orthopedics Today, noting there is a void in treatments for pain. “Especially, there is a void [in treatment] for chronic pain, particularly people with chronic low back, neck pain or other musculoskeletal conditions,” he said. To fill this void, he said many patients have turned to cannabis as a possible means to improve musculoskeletal pain management.

Although 33 states have approved comprehensive, publicly available medical marijuana or cannabis programs, Ronald J. Rapoport, MD, FACR, chief, division of rheumatology, Southcoast Health, said many physicians remain concerned about the legality of cannabinoids and any possible repercussions or criticisms they may face for recommending them to patients as a treatment.

Emily M. Lindley, PhD, said patients self-medicating with cannabis reported moderate to significant relief of their chronic spine pain. In addition, some evidence points to the potential of cannabinoids as an alternative to opioids, she said.

Source: Heather Cline

These concerns highlight the limited knowledge among the medical community on which cannabinoids are most effective for treatment of musculoskeletal pain, according to Rapoport, which may be due in part to a lack of proper clinical research.

“The number of properly done studies to review the effect of cannabinoids for pain, be it musculoskeletal pain or other pain, are not there yet,” Rapoport said. “There are some that are done and some that are positive and some that we are unsure of, but just the quality of the double-blind, placebo controlled study is not there.”

Cannabinoids of medical interest

Ari C. Greis, DO, director of the department of medical cannabis at Rothman Orthopaedic Institute, said there are more than 100 potentially active ingredients in the marijuana plant that could be used in treatment. Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the two main cannabinoids of medical interest, according to the National Institute on Drug Abuse (NIDA).

“THC [is] the psychoactive cannabinoid that leads to the euphoric effect that you typically think of with cannabis and ... CBD does not lead to that euphoric effect. CBD has been implicated in being involved in anti-inflammatory effects,” Emily M. Lindley, PhD, of University of Colorado – Anschutz Medical Campus, told Orthopedics Today.

According to Lindley, both THC and CBD bind to the endogenous cannabinoid receptors found in the endocannabinoid system. THC is a partial agonist of the CB1 and CB2 receptors and CBD is either a partial inverse agonist or antagonist at both, as well as a negative allosteric modulator at CB1 receptors, and their effects are different, she said.

“CBD can potentially block some of the effects of THC, which is why some people have hypothesized that CBD might be able to attenuate some of the psychoactive-type side effects of THC administration,” Lindley said.

Since cannabis is a schedule I substance and not approved as a safe and effective drug for any indication by the FDA, the cultivation of marijuana for research purposes is regulated by the Drug Enforcement Administration. To obtain marijuana, researchers must meet specific requirements listed on the NIDA website based on whether the research project is NIH funded. All marijuana used for research must be obtained from the University of Mississippi, which is the only institution that has been issued registration for the cultivation of marijuana for research.

“Unfortunately, even though our patients are regularly accessing all of these different varieties of topicals and oral medications at the dispensaries, we are not able to study them as researchers,” Lindley said.

Research into cannabinoids

Regardless of the process by which it is obtained, it is possible to obtain cannabis that is approved for research. With funding from the Colorado Department of Public Health and Environment, Lindley and her colleagues are studying the analgesic effects of vaporized cannabis, placebo cannabis, oxycodone and placebo oxycodone on patients with chronic back and neck pain.

“We are looking at subjective reports of the drug effects, such as psychoactive and mood, so [patients] tell us if they are feeling high or impaired, confused, anxious ... on different VAS scales,” Lindley said. “We are also looking at several tests of neurocognitive functioning. So they do a fine motor skill task, tasks on attention and concentration, memory ... and then we do standardized field sobriety tests, as well. Of course, we are also monitoring for any adverse events.”

Lindley noted they have recently received funding to perform a study on patients who are being tapered off high-dose opioids and will be randomized to receive either a THC/CBD combination therapy or a placebo. In addition to this study, the funding is also for a second study in which daily use of a THC/CBD combination will be compared with THC alone and with placebo for patients with chronic spine pain.

“I do not think we have the evidence at this point to say definitively one way or the other, but there is research that definitely suggests that [cannabinoids] could be an effective alternative to opioids and other traditional pain management tools,” Lindley said.

Lindley’s interest in researching the effect cannabinoids have on pain started in 2012 after noticing an increase in reports of self-treatment of chronic spine pain with cannabis from patients at their clinic. She and her colleagues surveyed 184 patients and discovered 19% of patients reported using cannabis for pain control.

“We also asked them about how they felt the cannabis worked for their pain compared to other medication,” Lindley said. “In general, 85% said they thought [cannabis] moderately or very much relieved their chronic spine pain. Then, we asked them about opioids specifically and 77% said [cannabis] worked at least as good as or better than their opioids.”

Jerome A. Schofferman

With little clinical evidence on how cannabinoids can be used in pain management, as more patients begin to use cannabinoids for pain management, Lindley said researchers should collect in a database information on what cannabinoids patients are using, as well as how and why they are using them. Such information will inform researchers and clinicians about the different conditions that may be treatable with cannabinoids, she said.

“We hear a lot about patients with osteoarthritis and rheumatoid arthritis using topicals for [treatment]. I am interested in that. I think that is something we definitely need to learn more about,” Lindley said.

Targeting musculoskeletal disorders

In addition to the stigma surrounding the use of cannabinoids, sources who spoke with Orthopedics Today said several unknowns surround the use of cannabinoids, including which patients may benefit the most from their use. Schofferman noted cannabinoids seem to be more effective for patients with chronic pain than acute pain.

“In patients who are using [cannabinoids] for chronic pain, it can also be useful for flares of the chronic pain, but it has not been studied much in acute pain and pain that goes away in a short period of time,” Schofferman said.

Greis said he has seen the benefits of cannabinoid use for various musculoskeletal disorders, including neuropathic pain, knee arthritis, degenerative joint disease, fibromyalgia or complex regional pain syndrome and in patients with ongoing pain after joint replacement.

“Patients we work with who have not found pain relief with medications, injections and therapy they have been offered ... are, frankly, desperate for relief and have tried lots of different things without success. Those are the people who I am offering an opportunity to try something new in a state where medical marijuana is legal and is approved for chronic pain,” said Greis, who is also clinical assistant professor of rehabilitation medicine at Thomas Jefferson University and senior fellow in the Institute of Emerging Health Professions and the Lambert Center for the Study of Medicinal Cannabis and Hemp.

Although in uncontrolled studies about 70% of patients say they experience pain relief with cannabinoids, according to Jason Friedrich, MD, the true rate of response to these compounds can be as low as 30% when compared to a non-active control group.

Jason Friedrich

“That ends up equating to basically needing to treat 24 or 25 people with [cannabinoids] to have one person get a response that is better than what a placebo would get you,” Friedrich, program director for the Pain Medicine Fellowship and assistant professor of physical medicine and rehabilitation at University of Colorado School of Medicine, told Orthopedics Today. “Right now, there is not definitive evidence that cannabis-based products will improve quality of life or physical function in people who are taking it specifically for pain management.”

Question of dosage

Friedrich said the current literature does not provide details on a therapeutic dose of cannabis for physicians to prescribe.

“I cannot tell a patient how much to use or how little to use, which is certainly challenging from a prescription standpoint,” he said.

A solution to the dosage question is for physicians to start by prescribing low dosages of cannabis and titrate up slowly to find tolerable dosages for each patient, Greis said, noting surgeons must also factor in the route of delivery of the cannabinoids, which include inhalation, a capsule, pill or edible, with a sublingual tincture or topical application.

“There are a variety of options, there are different routes of delivery, different cannabinoids, different ratios of CBD to THC and I think there are different ways to recommend it,” Greis told Orthopedics Today.

However, federal prohibition of cannabinoids has made it so physicians can certify that a patient has a medical condition that qualifies them to receive medical marijuana, but the physicians are not in control of which products their patients buy for treatment, he said.

“As a result, we have millions of people in this country who have access to legal marijuana and they are using it for medical purposes and/or recreational purposes and we do not have their own physicians controlling the dosages that they are getting,” Greis said. “It is creating another level of risk that is avoidable [by] changing of the scheduling of marijuana.”

Adverse events

Discussing the published literature, Greis noted chronic cannabis use does not cause lung cancer, head and neck cancer or end organ damage, such as kidney or liver disease. A literature review of more than 10,000 scientific abstracts performed by the National Academies of Sciences, Engineering and Medicine committee in 2017 also showed adults with chronic pain were more likely to experience a clinically significant reduction in pain symptoms with cannabinoid use.

But cannabinoids are not without adverse events, most of which are related to THC, Friedrich said.

Of concern is the risk for cannabis use disorder. Lindley said this occurs in about 10% of patients and affects adolescents more often than adults.

Cannabis use at a young age also may be associated with the development of schizophrenia or other mental health disorders, according to Greis. Therefore, patients with a family or personal history of mental health issues should not be prescribed cannabis.

“Overall, in adults who do not have a history of mental health issues, [cannabis] seems to be relatively safe, although we do not have a ton of long-term outcome data to comment on that specifically,” he said. “It seems to be safer than a lot of other pharmaceutical medications that are readily available.”

Educating physicians, patients

Sources who spoke with Orthopedics Today believe that cannabinoids may begin to play a bigger role in musculoskeletal health and pain management as it continues to be legalized throughout the United States.

Ronald J. Rapoport

“As long as we do not find any newly discovered side effects of concern—and there is no proof to that yet, at all—[cannabinoids] will continue to be advanced and we will learn to use [them] in a better way,” Rapoport said.

Friedrich said physicians who specialize in the treatment of pain should spend time now delving into the available research results to educate themselves on cannabinoids.

“At a basic level, this means being able to discriminate between CBD and THC to help patients understand how to identify various products and help them reduce risk of unexpected effects,” he said.

Cannabis knowledge, experience

Beyond that, Greis said orthopedic surgeons should attend lectures on the topic at scientific meetings, which can provide them with insights into the uses and effectiveness of cannabinoids.

“There are a number of online resources where physicians can get additional education on the topic. Then, a lot of it is just through experience by participating in a state medical marijuana program that gives physicians the opportunity to certify patients,” Greis said. “Oftentimes, what is the best way to learn is just to use common sense, give patients access and then see them in follow-up and discus how it is going.”

Ari C. Greis

Schofferman said physicians should keep an open mind regarding cannabis and provide information on its effects to their patients instead of immediately dismissing the patients’ inquiries about this treatment option.

“In that situation, the orthopedist should keep an open mind and say the truth: That it works in some people, but it is not a simple free ride,” Schofferman said. “There are definitely side effects that can happen, particularly psychoactive side effects. But, the overwhelming number of people who use it do not have serious adverse events. They have minor issues.”

He said cannabis should be used as an adjunctive treatment, not a substitute for rehabilitation, physical therapy or joint or spinal injections.

Despite the various possibilities and potential that surrounds cannabinoids, physicians need to understand that it is not a cure all for a patient’s pain, Friedrich said, noting that as more is learned about cannabinoids, physicians should not forget the foundational practices they have used for years that show favorable results for improving function and quality of life.

“[Although] cannabis may have a role for some patients, it only represents one aspect of comprehensive care, which should be rooted in more active, rather than passive treatments, such as exercise,” Friedrich said. “When something new comes along we cannot get away from our core principles on what keeps people moving. That being said, if I can use cannabis as a way of helping my patients meet their exercise goals or sleep better or participate better in physical therapy, then I am certainly willing to consider it.” – by Casey Tingle

Disclosures: Rapoport reports he is on the board of directors for Solar Therapeutics. Friedrich, Greis, Lindley and Schofferman report no relevant financial disclosures.

Click here to read the POINTCOUNTER, "How do you address patients’ questions on use of CBD oil for treatment of musculoskeletal pain?"

In 2018, WHO reported musculoskeletal conditions accounted for a greater proportion of persistent pain, with more than 150 diagnoses that affect the locomotor system. Although there are approved medications to treat musculoskeletal pain, sources who spoke with Orthopedics Today said these medications may not work or be suitable for all patients, especially for long term use, depending on their medical status.

“Even though [medications for musculoskeletal pain] can be effective, they are not effective for [some] people and they are not as safe as we would be led to believe,” Jerome A. Schofferman, MD, board certified in internal medicine and pain medicine, told Orthopedics Today, noting there is a void in treatments for pain. “Especially, there is a void [in treatment] for chronic pain, particularly people with chronic low back, neck pain or other musculoskeletal conditions,” he said. To fill this void, he said many patients have turned to cannabis as a possible means to improve musculoskeletal pain management.

Although 33 states have approved comprehensive, publicly available medical marijuana or cannabis programs, Ronald J. Rapoport, MD, FACR, chief, division of rheumatology, Southcoast Health, said many physicians remain concerned about the legality of cannabinoids and any possible repercussions or criticisms they may face for recommending them to patients as a treatment.

Emily M. Lindley, PhD, said patients self-medicating with cannabis reported moderate to significant relief of their chronic spine pain. In addition, some evidence points to the potential of cannabinoids as an alternative to opioids, she said.

Source: Heather Cline

These concerns highlight the limited knowledge among the medical community on which cannabinoids are most effective for treatment of musculoskeletal pain, according to Rapoport, which may be due in part to a lack of proper clinical research.

“The number of properly done studies to review the effect of cannabinoids for pain, be it musculoskeletal pain or other pain, are not there yet,” Rapoport said. “There are some that are done and some that are positive and some that we are unsure of, but just the quality of the double-blind, placebo controlled study is not there.”

Cannabinoids of medical interest

Ari C. Greis, DO, director of the department of medical cannabis at Rothman Orthopaedic Institute, said there are more than 100 potentially active ingredients in the marijuana plant that could be used in treatment. Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the two main cannabinoids of medical interest, according to the National Institute on Drug Abuse (NIDA).

PAGE BREAK

“THC [is] the psychoactive cannabinoid that leads to the euphoric effect that you typically think of with cannabis and ... CBD does not lead to that euphoric effect. CBD has been implicated in being involved in anti-inflammatory effects,” Emily M. Lindley, PhD, of University of Colorado – Anschutz Medical Campus, told Orthopedics Today.

According to Lindley, both THC and CBD bind to the endogenous cannabinoid receptors found in the endocannabinoid system. THC is a partial agonist of the CB1 and CB2 receptors and CBD is either a partial inverse agonist or antagonist at both, as well as a negative allosteric modulator at CB1 receptors, and their effects are different, she said.

“CBD can potentially block some of the effects of THC, which is why some people have hypothesized that CBD might be able to attenuate some of the psychoactive-type side effects of THC administration,” Lindley said.

Since cannabis is a schedule I substance and not approved as a safe and effective drug for any indication by the FDA, the cultivation of marijuana for research purposes is regulated by the Drug Enforcement Administration. To obtain marijuana, researchers must meet specific requirements listed on the NIDA website based on whether the research project is NIH funded. All marijuana used for research must be obtained from the University of Mississippi, which is the only institution that has been issued registration for the cultivation of marijuana for research.

“Unfortunately, even though our patients are regularly accessing all of these different varieties of topicals and oral medications at the dispensaries, we are not able to study them as researchers,” Lindley said.

Research into cannabinoids

Regardless of the process by which it is obtained, it is possible to obtain cannabis that is approved for research. With funding from the Colorado Department of Public Health and Environment, Lindley and her colleagues are studying the analgesic effects of vaporized cannabis, placebo cannabis, oxycodone and placebo oxycodone on patients with chronic back and neck pain.

“We are looking at subjective reports of the drug effects, such as psychoactive and mood, so [patients] tell us if they are feeling high or impaired, confused, anxious ... on different VAS scales,” Lindley said. “We are also looking at several tests of neurocognitive functioning. So they do a fine motor skill task, tasks on attention and concentration, memory ... and then we do standardized field sobriety tests, as well. Of course, we are also monitoring for any adverse events.”

PAGE BREAK

Lindley noted they have recently received funding to perform a study on patients who are being tapered off high-dose opioids and will be randomized to receive either a THC/CBD combination therapy or a placebo. In addition to this study, the funding is also for a second study in which daily use of a THC/CBD combination will be compared with THC alone and with placebo for patients with chronic spine pain.

“I do not think we have the evidence at this point to say definitively one way or the other, but there is research that definitely suggests that [cannabinoids] could be an effective alternative to opioids and other traditional pain management tools,” Lindley said.

Lindley’s interest in researching the effect cannabinoids have on pain started in 2012 after noticing an increase in reports of self-treatment of chronic spine pain with cannabis from patients at their clinic. She and her colleagues surveyed 184 patients and discovered 19% of patients reported using cannabis for pain control.

“We also asked them about how they felt the cannabis worked for their pain compared to other medication,” Lindley said. “In general, 85% said they thought [cannabis] moderately or very much relieved their chronic spine pain. Then, we asked them about opioids specifically and 77% said [cannabis] worked at least as good as or better than their opioids.”

Jerome A. Schofferman

With little clinical evidence on how cannabinoids can be used in pain management, as more patients begin to use cannabinoids for pain management, Lindley said researchers should collect in a database information on what cannabinoids patients are using, as well as how and why they are using them. Such information will inform researchers and clinicians about the different conditions that may be treatable with cannabinoids, she said.

“We hear a lot about patients with osteoarthritis and rheumatoid arthritis using topicals for [treatment]. I am interested in that. I think that is something we definitely need to learn more about,” Lindley said.

Targeting musculoskeletal disorders

In addition to the stigma surrounding the use of cannabinoids, sources who spoke with Orthopedics Today said several unknowns surround the use of cannabinoids, including which patients may benefit the most from their use. Schofferman noted cannabinoids seem to be more effective for patients with chronic pain than acute pain.

“In patients who are using [cannabinoids] for chronic pain, it can also be useful for flares of the chronic pain, but it has not been studied much in acute pain and pain that goes away in a short period of time,” Schofferman said.

PAGE BREAK

Greis said he has seen the benefits of cannabinoid use for various musculoskeletal disorders, including neuropathic pain, knee arthritis, degenerative joint disease, fibromyalgia or complex regional pain syndrome and in patients with ongoing pain after joint replacement.

“Patients we work with who have not found pain relief with medications, injections and therapy they have been offered ... are, frankly, desperate for relief and have tried lots of different things without success. Those are the people who I am offering an opportunity to try something new in a state where medical marijuana is legal and is approved for chronic pain,” said Greis, who is also clinical assistant professor of rehabilitation medicine at Thomas Jefferson University and senior fellow in the Institute of Emerging Health Professions and the Lambert Center for the Study of Medicinal Cannabis and Hemp.

Although in uncontrolled studies about 70% of patients say they experience pain relief with cannabinoids, according to Jason Friedrich, MD, the true rate of response to these compounds can be as low as 30% when compared to a non-active control group.

Jason Friedrich

“That ends up equating to basically needing to treat 24 or 25 people with [cannabinoids] to have one person get a response that is better than what a placebo would get you,” Friedrich, program director for the Pain Medicine Fellowship and assistant professor of physical medicine and rehabilitation at University of Colorado School of Medicine, told Orthopedics Today. “Right now, there is not definitive evidence that cannabis-based products will improve quality of life or physical function in people who are taking it specifically for pain management.”

Question of dosage

Friedrich said the current literature does not provide details on a therapeutic dose of cannabis for physicians to prescribe.

“I cannot tell a patient how much to use or how little to use, which is certainly challenging from a prescription standpoint,” he said.

A solution to the dosage question is for physicians to start by prescribing low dosages of cannabis and titrate up slowly to find tolerable dosages for each patient, Greis said, noting surgeons must also factor in the route of delivery of the cannabinoids, which include inhalation, a capsule, pill or edible, with a sublingual tincture or topical application.

“There are a variety of options, there are different routes of delivery, different cannabinoids, different ratios of CBD to THC and I think there are different ways to recommend it,” Greis told Orthopedics Today.

PAGE BREAK

However, federal prohibition of cannabinoids has made it so physicians can certify that a patient has a medical condition that qualifies them to receive medical marijuana, but the physicians are not in control of which products their patients buy for treatment, he said.

“As a result, we have millions of people in this country who have access to legal marijuana and they are using it for medical purposes and/or recreational purposes and we do not have their own physicians controlling the dosages that they are getting,” Greis said. “It is creating another level of risk that is avoidable [by] changing of the scheduling of marijuana.”

Adverse events

Discussing the published literature, Greis noted chronic cannabis use does not cause lung cancer, head and neck cancer or end organ damage, such as kidney or liver disease. A literature review of more than 10,000 scientific abstracts performed by the National Academies of Sciences, Engineering and Medicine committee in 2017 also showed adults with chronic pain were more likely to experience a clinically significant reduction in pain symptoms with cannabinoid use.

But cannabinoids are not without adverse events, most of which are related to THC, Friedrich said.

Of concern is the risk for cannabis use disorder. Lindley said this occurs in about 10% of patients and affects adolescents more often than adults.

Cannabis use at a young age also may be associated with the development of schizophrenia or other mental health disorders, according to Greis. Therefore, patients with a family or personal history of mental health issues should not be prescribed cannabis.

“Overall, in adults who do not have a history of mental health issues, [cannabis] seems to be relatively safe, although we do not have a ton of long-term outcome data to comment on that specifically,” he said. “It seems to be safer than a lot of other pharmaceutical medications that are readily available.”

Educating physicians, patients

Sources who spoke with Orthopedics Today believe that cannabinoids may begin to play a bigger role in musculoskeletal health and pain management as it continues to be legalized throughout the United States.

Ronald J. Rapoport

“As long as we do not find any newly discovered side effects of concern—and there is no proof to that yet, at all—[cannabinoids] will continue to be advanced and we will learn to use [them] in a better way,” Rapoport said.

Friedrich said physicians who specialize in the treatment of pain should spend time now delving into the available research results to educate themselves on cannabinoids.

“At a basic level, this means being able to discriminate between CBD and THC to help patients understand how to identify various products and help them reduce risk of unexpected effects,” he said.

PAGE BREAK

Cannabis knowledge, experience

Beyond that, Greis said orthopedic surgeons should attend lectures on the topic at scientific meetings, which can provide them with insights into the uses and effectiveness of cannabinoids.

“There are a number of online resources where physicians can get additional education on the topic. Then, a lot of it is just through experience by participating in a state medical marijuana program that gives physicians the opportunity to certify patients,” Greis said. “Oftentimes, what is the best way to learn is just to use common sense, give patients access and then see them in follow-up and discus how it is going.”

Ari C. Greis

Schofferman said physicians should keep an open mind regarding cannabis and provide information on its effects to their patients instead of immediately dismissing the patients’ inquiries about this treatment option.

“In that situation, the orthopedist should keep an open mind and say the truth: That it works in some people, but it is not a simple free ride,” Schofferman said. “There are definitely side effects that can happen, particularly psychoactive side effects. But, the overwhelming number of people who use it do not have serious adverse events. They have minor issues.”

He said cannabis should be used as an adjunctive treatment, not a substitute for rehabilitation, physical therapy or joint or spinal injections.

Despite the various possibilities and potential that surrounds cannabinoids, physicians need to understand that it is not a cure all for a patient’s pain, Friedrich said, noting that as more is learned about cannabinoids, physicians should not forget the foundational practices they have used for years that show favorable results for improving function and quality of life.

“[Although] cannabis may have a role for some patients, it only represents one aspect of comprehensive care, which should be rooted in more active, rather than passive treatments, such as exercise,” Friedrich said. “When something new comes along we cannot get away from our core principles on what keeps people moving. That being said, if I can use cannabis as a way of helping my patients meet their exercise goals or sleep better or participate better in physical therapy, then I am certainly willing to consider it.” – by Casey Tingle

PAGE BREAK

Disclosures: Rapoport reports he is on the board of directors for Solar Therapeutics. Friedrich, Greis, Lindley and Schofferman report no relevant financial disclosures.

Click here to read the POINTCOUNTER, "How do you address patients’ questions on use of CBD oil for treatment of musculoskeletal pain?"