Why Cannabis Holds Promise for Pain Management

By Benjamin Land, University of Washington Center for Cannabis Research

Drug overdose deaths from opioids continue to rise in the U.S. as a result of both the misuse of prescription opioids and the illicit drug market.

But an interesting trend has developed: Opioid emergency room visits drop by nearly 8% and opioid prescriptions are modestly lower in states where marijuana is legalized.

Marijuana is produced by the cannabis plant, which is native to Asia but is now grown throughout the world. Individuals use marijuana for both its psychoactive, euphoria-inducing properties and its ability to relieve pain.

Chemicals produced by the cannabis plant are commonly known as cannabinoids. The two primary cannabinoids that occur naturally in the cannabis plant are THC – the psychoactive compound in marijuana – and CBD, which does not cause the sensation of being high.

Many marijuana users say they take it to treat pain, suggesting that readily available cannabinoids could potentially be used to offset the use of opioids such as morphine and oxycodone that are commonly used in pain treatment. A safer, natural alternative to opioid painkillers would be an important step toward addressing the ongoing opioid epidemic.

Intriguingly however, research suggests that cannabis use could also lessen the need for opioids directly by interacting with the body’s own natural opioid system to produce similar pain-relief effects.

I am a neuropharmacology scientist who studies both opioids and cannabinoids as they relate to pain treatment and substance abuse. My research focuses on the development of drug compounds that can provide chronic pain relief without the potential for overuse and without the tapering off of effectiveness that often accompanies traditional pain medications.

How Opioids Work

Our bodies have their own built-in opioid system that can aid in managing pain. These opioids, such as endorphins, are chemicals that are released when the body experiences stress such as strenuous exercise, as well as in response to pleasurable activities like eating a good meal. But it turns out that humans are not the only organisms that can make opioids.

In the 1800s, scientists discovered that the opioid morphine – isolated from opium poppy – was highly effective at relieving pain. In the last 150 years, scientists have developed additional synthetic opioids like hydrocodone and dihydrocodeine that also provide pain relief.

Other opioids like heroin and oxycodone are very similar to morphine, but with small differences that influence how quickly they act on the brain. Fentanyl has an even more unique chemical makeup. It is the most powerful opioid and is the culprit behind the current surge in drug overdoses and deaths, including among young people.

Opioids, whether naturally produced or synthetic, produce pain relief by binding to specific receptors in the body, which are proteins that act like a lock that can only be opened by an opioid key.

One such receptor, known as the mu-opioid receptor, is found on pain-transmitting nerve cells along the spinal cord. When activated, mu-receptors tamp down the cell’s ability to relay pain information. Thus, when these opioids are circulating in the body and they reach their receptor, stimuli that would normally cause pain are not transmitted to the brain.

These same receptors are also found in the brain. When opioids find their receptor, the brain releases dopamine – the so-called “feel-good” chemical – which has its own receptors. This is in part why opioids can be highly addicting. Research suggests that these receptors drive the brain’s reward system and promote further drug-seeking. For people who are prescribed opiates, this creates the potential for abuse.

Opioid drugs, which include heroin, oxycodone and fentanyl, are highly addictive.

Opioid receptors are dynamically regulated, meaning that as they get exposed to more and more opioids, the body adapts quickly by deactivating the receptor. In other words, the body needs more and more of that opioid to get pain relief and to produce the feel-good response. This process is known as tolerance. The drive to seek more and more reward paired with an ever-increasing tolerance is what leads to the potential for overdose, which is why opioids are generally not long-term solutions for pain.

How THC and CBD Relieve Pain

Both THC and CBD have been shown in numerous studies to lessen pain, though – importantly – they differ in which receptors they bind to in order to produce these effects.

THC binds to cannabinoid receptors that are located throughout the central nervous system, producing a variety of responses. One of those responses is the high associated with cannabis use, and another is pain relief. Additionally, THC is believed to reduce inflammation in a manner similar to anti-inflammatory drugs like ibuprofen.

In contrast, CBD appears to bind to several distinct receptors, and many of these receptors can play a role in pain reduction. Importantly, this occurs without the high that occurs with THC.

Because they target different receptors, THC and CBD may be more effective working in concert rather than alone, but more studies in animal models and humans are needed.

Cannabinoids may also be helpful for other conditions as well. Many studies have demonstrated that cannabinoid drugs approved for medical use are effective for pain and other symptoms like spasticity, nausea and appetite loss.

Along with the pairing of THC and CBD, researchers are beginning to explore the use of those two cannabinoids together with existing opioids for pain management. This research is being done in both animal models and humans.

These studies are designed to understand both the benefits – pain relief – and risks – primarily addiction potential – of co-treatment with cannabinoids and opioids. The hope would be that THC or CBD may lower the amount of opioid necessary for powerful pain relief without increasing addiction risk.

For example, one study tested the combination of smoked cannabis and oxycontin for pain relief and reward. It found that co-treatment enhanced pain relief but also increased the pleasure of the drugs. This, as well as a limited number of other studies, suggests there may not be a net benefit.

However, many more studies of this type will be necessary to understand if cannabinoids and opioids can be safely used together for pain. Still, using cannabinoids as a substitution for opioids remains a promising pain treatment strategy.

The next decade of research will likely bring important new insights to the therapeutic potential of cannabinoids for chronic pain management. And as marijuana legalization continues to spread across the U.S., its use in medicine will undoubtedly grow exponentially.

Benjamin Land, PhD is a Research Associate Professor of Pharmacology at the University of Washington School of Medicine and the UW Center for Cannabis Research. Land receives funding from the National Institutes of Health for cannabinoid research, and has received cannabinoid related funding from the University of Washington Addiction and Drug Abuse Institute and SCAN Design Foundation.

This article originally appeared in The Conversation and is republished with permission.

Why Some Drugs Work Better on Different Types of Pain

By Dr. Rebecca Seal and Dr. Benedict Alder

Without the ability to feel pain, life is more dangerous. To avoid injury, pain tells us to use a hammer more gently, wait for the soup to cool or put on gloves in a snowball fight. Those with rare inherited disorders that leave them without the ability to feel pain are unable to protect themselves from environmental threats, leading to broken bones, damaged skin, infections and ultimately a shorter life span.

In these contexts, pain is much more than a sensation: It is a protective call to action. But pain that is too intense or long-lasting can be debilitating. So how does modern medicine soften the call?

As a neurobiologist and an anesthesiologist who study pain, this is a question we and other researchers have tried to answer. Science’s understanding of how the body senses tissue damage and perceives it as pain has progressed tremendously over the past several years. It has become clear that there are multiple pathways that signal tissue damage to the brain and sound the pain alarm bell.

Interestingly, while the brain uses different pain signaling pathways depending on the type of damage, there is also redundancy to these pathways. Even more intriguing, these neural pathways morph and amplify signals in the case of chronic pain and pain caused by conditions affecting nerves themselves, even though the protective function of pain is no longer needed.

Painkillers work by tackling different parts of these pathways. Not every painkiller works for every type of pain, however. Because of the multitude and redundancy of pain pathways, a perfect painkiller is elusive. But in the meantime, understanding how existing painkillers work helps medical providers and patients use them for the best results.

Anti-Inflammatories

A bruise, sprain or broken bone from an injury all lead to tissue inflammation, an immune response that can lead to swelling and redness as the body tries to heal. Specialized nerve cells in the area of the injury called nociceptors sense the inflammatory chemicals the body produces and send pain signals to the brain.

Common over-the-counter anti-inflammatory painkillers work by decreasing inflammation in the injured area. These are particularly useful for musculoskeletal injuries or other pain problems caused by inflammation such as arthritis.

Nonsteroidal anti-inflammatories like ibuprofen (Advil, Motrin), naproxen (Aleve) and aspirin do this by blocking an enzyme called COX that plays a key role in a biochemical cascade that produces inflammatory chemicals. Blocking the cascade decreases the amount of inflammatory chemicals, and thereby reduces the pain signals sent to the brain.

While acetaminophen (Tylenol), also known as paracetamol, doesn’t reduce inflammation as NSAIDs do, it also inhibits COX enzymes and has similar pain-reducing effects. Prescription anti-inflammatory painkillers include other COX inhibitors, corticosteroids and, more recently, drugs that target and inactivate the inflammatory chemicals themselves. Aspirin and ibuprofen work by blocking the COX enzymes that play a key role in pain-causing processes.

Because inflammatory chemicals are involved in other important physiological functions beyond just sounding the pain alarm, medications that block them will have side effects and potential health risks, including irritating the stomach lining and affecting kidney function. Over-the-counter medications are generally safe if the directions on the bottle are followed strictly.

Corticosteroids like prednisone block the inflammatory cascade early on in the process, which is probably why they are so potent in reducing inflammation. However, because all the chemicals in the cascade are present in nearly every organ system, long-term use of steroids can pose many health risks that need to be discussed with a physician before starting a treatment plan.

Topical Medications

Many topical medications target nociceptors, the specialized nerves that detect tissue damage. Local anesthetics, like lidocaine, prevent these nerves from sending electrical signals to the brain.

The protein sensors on the tips of other sensory neurons in the skin are also targets for topical painkillers. Activating these proteins can elicit particular sensations that can lessen the pain by reducing the activity of the damage-sensing nerves, like the cooling sensation of menthol or the burning sensation of capsaicin.

Because these topical medications work on the tiny nerves in the skin, they are best used for pain directly affecting the skin. For example, a shingles infection can damage the nerves in the skin, causing them to become overactive and send persistent pain signals to the brain. Silencing those nerves with topical lidocaine or an overwhelming dose of capsaicin can reduce these pain signals.

Nerve Injury Medications

Nerve injuries, most commonly from arthritis and diabetes, can cause the pain-sensing part of the nervous system to become overactive. These injuries sound the pain alarm even in the absence of tissue damage. The best painkillers in these conditions are those that dampen that alarm.

Antiepileptic drugs, such as gabapentin (Neurontin), suppress the pain-sensing system by blocking electrical signaling in the nerves. However, gabapentin can also reduce nerve activity in other parts of the nervous system, potentially leading to sleepiness and confusion.

Antidepressants, such as duloxetine and nortriptyline, are thought to work by increasing certain neurotransmitters in the spinal cord and brain involved in regulating pain pathways. But they may also alter chemical signaling in the gastrointestinal tract, leading to an upset stomach.

All these medications are prescribed by doctors.

Opioids

Opioids are chemicals found or derived from the opium poppy. One of the earliest opioids, morphine, was purified in the 1800s. Since then, medical use of opioids has expanded to include many natural and synthetic derivatives of morphine with varying potency and duration. Some common examples include codeine, tramadol, hydrocodone, oxycodone, buprenorphine and fentanyl.

Opioids decrease pain by activating the body’s endorphin system. Endorphins are a type of opioid your body naturally produces that decreases incoming signals of injury and produces feelings of euphoria – the so-called “runner’s high.” Opioids simulate the effects of endorphins by acting on similar targets in the body.

While opioids can provide strong pain relief, they are not meant for long-term use because they are addictive.

Although opioids can decrease some types of acute pain, such as after surgery, musculoskeletal injuries like a broken leg or cancer pain, they are often ineffective for neuropathic injuries and chronic pain.

Because the body uses opioid receptors in other organ systems like the gastrointestinal tract and the lungs, side effects and risks include constipation and potentially fatal suppression of breathing. Prolonged use of opioids may also lead to tolerance, where more drug is required to get the same painkilling effect. This is why opioids can be addictive and are not intended for long-term use. All opioids are controlled substances and are carefully prescribed by doctors because of these side effects and risks.

Cannabinoids

Although cannabis has received a lot of attention for its potential medical uses, there isn’t sufficient evidence available to conclude that it can effectively treat pain. Since the use of cannabis is illegal at the federal level in the U.S., high-quality clinical research funded by the federal government has been lacking.

Researchers do know that the body naturally produces endocannabinoids, a form of the chemicals in cannabis, to decrease pain perception. Cannabinoids may also reduce inflammation. Given the lack of strong clinical evidence, physicians typically don’t recommend them over FDA-approved medications.

Matching Pain to Drug

While sounding the pain alarm is important for survival, dampening the klaxon when it’s too loud or unhelpful is sometimes necessary.

No existing medication can perfectly treat pain. Matching specific types of pain to drugs that target specific pathways can improve pain relief, but even then, medications can fail to work even for people with the same condition. More research that deepens the medical field’s understanding of the pain pathways and targets in the body can help lead to more effective treatments and improved pain management.

Rebecca Seal, PhD, is an Associate Professor of Neurobiology at University of Pittsburgh Health Sciences. Benedict Alter, MD, is an Assistant Professor of Anesthesiology and Perioperative Medicine, at University of Pittsburgh Health Sciences.

This article originally appeared in The Conservation and is republished with permission.

Can Medical Cannabis Treat Acute Pain?

By Pat Anson, PNN Editor

Medical cannabis is often touted as a treatment for chronic pain, but surprisingly little is known about its effectiveness in treating short-term, acute pain – like a toothache or post-operative pain.

In a new systematic review published in the journal Cannabis and Cannabinoid Research, Canadian researchers found there was a small but meaningful reduction in pain scores with medical cannabis compared to placebo in patients experiencing acute pain.

Researchers at McMaster University and Northern Ontario School of Medicine reviewed 25 clinical studies dealing with cannabis and acute pain, but could find only six that met their criteria for size and quality.

Five of the studies dealt with the oral administration of cannabinoids, while the sixth involved the intramuscular injection of levonantradol -- a potent synthetic cannabinoid used in research -- that was given to 56 patients suffering from post-operative or trauma pain.

Interestingly, while that study was conducted nearly 40 years ago, the levonantradol injections were found to be the most effective method for administering cannabinoids for acute pain.

“There is low-quality evidence indicating that cannabinoids may be a safe alternative for a small but significant reduction in subjective pain score when treating acute pain, with intramuscular administration resulting in a greater reduction relative to oral,” said co-author Herman Johal, MD, a researcher and orthopedic trauma surgeon at McMaster University.

“There was a significant difference in the effect size between oral and nonoral routes of administration. This indicated that there may be differences in efficacy for acute pain based on route of administration.”

Johal and his colleagues say the oral absorption of cannabinoids is slow and can take hours before there is any pain relief – which is not ideal for someone recovering from surgery. Inhaled cannabinoids work much faster – about ten minutes – but may not be suitable in a hospital setting.

In short, while cannabinoids show some promise in treating acute pain, a lot more research is needed.

“Our review highlights the need for further research to investigate the optimal route and composition of cannabinoids in the acute pain setting, including large, high-quality randomized clinical trials to better understand the risks and benefits of cannabinoids in this patient population,” Johal wrote.

Common adverse effects from cannabinoids in the acute pain studies included nausea and dizziness.

Tolerance Reduces Sleep Benefits of Medical Cannabis

By Pat Anson, PNN Editor

Getting a good night’s sleep can be a godsend to someone suffering from chronic pain. That’s why many pain patients are experimenting with medical cannabis to help manage their sleep problems.

But a small new study found that while cannabis initially helps with sleep, regular use leads to drug tolerance that causes even more sleep problems. A second study raises doubts about the use of cannabinoids in treating cancer pain.

Researchers at the Rambam Institute for Pain Medicine in Israel enrolled 129 volunteers over age 50 with chronic neuropathic pain. About half used medical cannabis for at least a year, either by smoking (69%), oil extracts (21%) or vaporizers (20%). The other half did not use cannabis.

Sleep problems were common among both groups of patients, with about 3 out 4 having trouble falling asleep or staying asleep.

Researchers found that cannabis users were less likely to wake up during the night, compared to those who did not use the drug. But over time the benefits of cannabis were reversed, and frequent users found it harder to fall asleep and woke up more often during the night.

The findings are published in the British Medical Journal's Supportive and Palliative Care journal.

“This study is among the first to test the link between whole plant MC (medical cannabis) use and sleep quality. In our sample of older (50+ years) chronic pain patients we found that MC may be related to fewer awakenings at night. Yet patients may also develop tolerance to the sleep-aid characteristics of MC,” researchers wrote.

“These findings may have large public health impacts considering the ageing of the population, the relatively high prevalence of sleep problems in this population along with increasing use of MC.”

The study was observational and did not establish a direct causal link between cannabis and sleep.  Another weakness is that the specific timing of cannabis use by participants was unknown. Taking cannabis before bedtime may have a stronger association with sleep. The researchers said their findings were preliminary and more larger studies were needed.

Cannabinoids Not Recommended for Cancer Pain

Another study published in the same medical journal found that cannabinoids do not reduce pain in patients with advanced cancer.

Researchers at the University of Hull in the UK reviewed data from five high-quality clinical studies involving 1,442 cancer patients and found that pain intensity was no different between those taking cannabinoids and those given a placebo.

Patients using cannabinoids also had nearly twice the risk of short-term side effects such as dizziness, drowsiness, nausea and fatigue. They were also more likely to drop out of studies.  

“For a medication to be useful, there needs to be a net overall benefit, with the positive effects (analgesia) outweighing adverse effects. None of the included phase III studies show benefit of cannabinoids,” researchers concluded.

“When statistically pooled, there was no decrease in pain score from cannabinoids. There are, however, significant adverse effects and dropouts reported from cannabinoids. Based on evidence with a low risk of bias, cannabinoids cannot be recommended for the treatment of cancer-related pain.”

The American Cancer Society takes a different view, pointing out that studies have found marijuana smoking can be helpful in treating nausea from cancer chemotherapy.  Other studies have also suggested that THC, CBD and other cannabinoids slow the growth of cancer cells in a laboratory setting.

Medical marijuana is legal in 33 In U.S. states and cancer is recognized as a qualifying condition in many of them.

Questioning the New Cannabinoids

By Roger Chriss, PNN Columnist

A new cannabinoid similar to THC was announced last month in Scientific Reports. Dubbed tetrahydrocannabiphorol, or THCP for short, it is being hailed as a “breakthrough discovery” that is 30 times stronger than THC, the chemical compound in cannabis that causes euphoria.

Discovered by a group of Italian researchers, THCP has been shown to have a high affinity for the cannabinoid receptor (CB1) in the brain. Cinzia Citti from the Institute of Nanotechnology told Medical Cannabis Network that THCP likely has pain relieving effects, but pharmacological studies are needed to confirm it.

“Once all pharmacological profile of THCP has been established, I can imagine that THCP-rich cannabis varieties will be developed in the future for specific pathologies,” Citti said.

THCP’s chemical structure makes it nearly optimal for activity at the CB1 receptor. Studies on mice showed that THCP has psychoactive effects at low doses, but research is required to confirm how strongly THCP acts on the human brain.

‘Potential Game Changer’

There is already great enthusiasm for THCP, as well as cannabidiphorol (CBDP), another newly identified cannabinoid compound.

Vice states that “it’s possible these chemicals could treat certain conditions better than their counterparts,” THC and CBD.

Leafly went even further, predicting the new cannabinoids could have “immense therapeutic implications,” with THCP being a “potential game changer.”

Looking beyond the media hype, there appears to be no critical consideration of what a cannabinoid 30 times more potent than THC might mean. THC Is known to have significant negative effects on the human body. The National Institute on Drug Abuse lists side effects such as impaired breathing, increased heart rate, and mental effects such as hallucinations, paranoia and schizophrenia.

Moreover, THC is addictive. Health Canada reports that 1 out of 10 people who use cannabis will develop an addiction. The addiction odds increase to 1 out of 2 for people who use cannabis daily.

In other words, is THCP going to be 30 times more additive than THC? Will it cause 30 times more cognitive impairment? A 30-fold increase in ER visits and hospital admissions?

If THCP acts much more strongly on the CB1 receptor, then it may not really be a good thing for cannabis users or public health. These questions may seem absurd, but potent synthetic cannabinoids like K2/Spice have been a public health concern for many years. THCP may also have unknown side effects.

The difference between THC and CBD comes down to one chemical bond, but their respective effects are quite different. The apparent similarities between THCP and THC cannot be used to draw conclusions about effects in humans, good or bad.  

At present, very little is known about THCP. As Live Science points out, "while THC offers some medicinal effects, including pain and nausea relief, no one knows if THCP has these qualities."

It would be nice if even just one media outlet had mentioned the THCP could have some of the same problems that THC does, and at far lower concentrations.

Roger Chriss lives with Ehlers Danlos syndrome and is a proud member of the Ehlers-Danlos Society. Roger is a technical consultant in Washington state, where he specializes in mathematics and research. 

Is It Safe to Use Cannabis with THC?

By Ellen Lenox Smith, Columnist

I am constantly reading about people interested in medical marijuana who are seeking information on cannabis products high in CBD for their medical issues.  I’ve also noticed many stating they do not want any THC in these products.

I’ve found that I need both. 

Tetrahydrocannabinol (THC) and cannabidiol (CBD) are chemical compounds, called cannabinoids, found in the marijuana plant. There are well over a hundred different cannabinoids in marijuana, and they all interact with receptors in the brain and body, causing various effects.

THC is the most widely known cannabinoid, due to its abundance and psychoactive qualities. For centuries, marijuana has been used recreationally because of THC’s ability to make people feel “high” or euphoric.

But as cannabis has become more accepted for medical use, some are concerned that they will get high or stoned if their cannabis has any THC in it. Many have turned to cannabis products that primarily contain CBD. 

Personally, I have learned to look for products that contain both THC and CBD, as they are more effective in easing my pain and helping me sleep.

DRUG POLICY ALLIANCE

Personally, I have learned to look for products that contain both THC and CBD, as they are more effective in easing my pain and helping me sleep.

Many patients became interested in CBD after learning that epileptic seizures could be reduced or even stopped by utilizing cannabis products high in CBD content.  This was discovered when the parents of Charlotte Figi, a 5-year old girl suffering from severe seizures, learned of a cannabis strain that was loaded with CBD. This was what they wanted to try with their daughter, because it was completely non-psychoactive, unlike THC. The results were amazing, not only reducing Charlotte’s seizures, but also opening up the possibility of helping patients with other conditions such as spasms, anxiety and chronic pain.

Like me, many patients with chronic conditions have found that they need to use medical cannabis extracted from either a high CBD variety or one with more THC. If you find a high-CBD strain, it does not mean it will be THC-free. Many strains advertised as “high-CBD” still contain some psychoactive cannabinoids. This should not scare you.

I am 67 years old and have been using cannabis since 2007 for two incurable painful conditions.   Like many patients, I had no desire to experience the psychoactive effects of THC, so at one point in my treatment I tried a high CBD strain containing only trace amounts of THC. The pain relief just didn’t happen, so I switched back to cannabis products that combined CBD and THC.

Recently, after reading that CBD can help with cancer, lupus, nicotine addiction, Parkinson’s disease, osteoporosis and other chronic conditions, I decided to grow plants high in CBD to add to the oil I take orally at night. I now make an oil with a combination of strains that include this higher CBD strain, along with higher THC plants.

I want you to know that I do not get “high” or stoned, as some assume. What I get is pain relief.

But remember, as with any medication, you can take too much and get a negative reaction, so be careful to take the dose that is right for you. Don’t be concerned if you are like me and need THC to get relief from your pain. Each body requires something different and we all need to find the correct match for safe relief.

Ellen Lenox Smith suffers from Ehlers Danlos syndrome and sarcoidosis. Ellen and her husband Stuart live in Rhode Island. They are co-directors for medical marijuana advocacy for the U.S. Pain Foundation and serve as board members for the Rhode Island Patient Advocacy Coalition.

For more information about medical marijuana, visit their website.

The information in this column should not be considered as professional medical advice, diagnosis or treatment. It is for informational purposes only and represents the author’s opinions alone. It does not inherently express or reflect the views, opinions and/or positions of Pain News Network.