Part II — In a Bad Way: Pain, Cannabis and Opioids – Types of Pain and How Cannabis Works to Relieve It

People hurt in different ways and from different causes so I’ll start with a brief primer on the three basic types of pain – nociceptive, neuropathic and central.

Inflammatory Pain (Nociceptive)

Think of nociceptive pain as the garden variety inflammatory pain that every weekend warrior has experienced. It can be sharp, achy, tender or throbbing depending upon the tissue damage location and extent. Before you reach for the Advil and an ice pack, your tissues get busy recruiting inflammatory and immune cells to repair the damage.  In turn, the cells release proteins and chemicals that activate receptors on nerves that make their way into the spinal cord and up to the brain.  When the brain gets involved, the sensation of pain begins.

Neuropathic Pain

Neuropathic pain is a different animal. As its name suggests, neuropathic pain arises from damage to the body’s nervous system.  It’s more common than you think, affecting some seven to ten percent of the population.  Nerve pain can result from a forceful injury like pinching or stabbing.   But more patients know neuropathic pain from underlying diseases such as Parkinson’s disease, diabetes, shingles and multiple sclerosis.

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Central Pain

Central pain is trickier to describe and the hardest to treat.  It’s defined as a neurological condition caused by damage to or dysfunction of the central nervous system (CNS), which includes the brain, brainstem and spinal cord. It can be caused by disease, tumors, or by brain or spinal cord trauma.  Because of the variety of causes, central pain differs widely from patient to patient.  It may affect a large portion of the body or may be more restricted to specific areas, such as hands or feet.

When I worked in brain injury rehabilitation, central pain for those we cared for was common and unrelenting, made worse by touch, movement, emotions, and temperature changes.  Patients would tell me that they felt “pins and needles” or a burning sensation in their hands or feet that would make moving, even in bed, terribly difficult.   Sometimes central pain results from an injury but it can often arise in the absence of any known cause.  Fibromyalgia, a classic example of central pain, comes from dysfunction in the way pain signals make their way to the brain and are processed.

How Cannabis Spells Relief

The Downside of NSAIDS

Although cannabis is fairly well-known as a pain relief treatment, it is rarely the first drug that a patient takes to mitigate pain.  Most of us shop for one of the abundant drugstore varieties of Ibuprofen and Naproxen known as nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDS inhibit pain by addressing local tissue inflammation, blocking an enzyme called cyclooxygenase (COX), which is required to make the blood vessels dilate.  They can be used daily for prolonged periods to manage inflammatory conditions, whether it’s due to arthritis or a sprained ankle, but they are not without their side effects when used frequently.    One patient told me that she ended up in the ER after taking a nightly dose of Ibuprofen to help her aches and pains.  Eventually this led to a nasty bleed in the gastro-intestinal tract and a stern warning from her physician to curb her seemingly- innocuous Advil usage immediately.

Considering Cannabis for Inflammation

Why would cannabis help diminish inflammatory pain?  For starters, cannabis turns on pain inhibition.  Both CBD and THC cannabinoids reduce the pain signals at the site of injury by blocking the inflammatory process itself.  Then, as pain signals try to make their way up the spinal cord to the brain, THC activates the body’s built-in CB1 and CB2 cells, mitigating the body’s pain-inducing response to injury. CBD reduces inflammation by both blocking inflammatory mediators and activating the helpful repair cells known as macrophages from the pro-inflammatory type to the anti-inflammatory type.  It’s like playing a little trick on the brain by making it a little less sensitized to a process that ordinarily is hurtful.

Calming Nerve Pain with Cannabis

Neuropathic pain, on the other hand, may not respond at all to anti-inflammatory drugs so patients and their health care providers commonly struggle to find a safe and effective form of relief – usually in the form of prescriptive drugs like anti-depressants and anti-convulsants.  But again, cannabis comes to the rescue of many who suffer nerve-related pain by turning on cannabinoid receptors in the peripheral nerves.   A good example is sciatica, a painful condition in which the pinching of the sciatic nerve starts a chain reaction of pain radiating from the lower back down the leg.   Cannabis works for a sciatica patient by increasing the CB1 receptors along the spinal cord pathway which in turn reduce pain.  Relieving neuropathic pain by weakening the strength of pain signals in the spinal cord and how they are processed in the brain is powerful since is can address such a vexing and wide-ranging spate of diseases and injuries.  Just ask anyone who’s had a bad case of shingles.

Central Pain Case in Point: Fibromyalgia

In the area of central pain, the most intense subject of research is how cannabis might help patients with fibromyalgia, a complicated and often misdiagnosed disease.  Affecting some 10 million people in the U.S. alone, fibromyalgia is a common condition that affects the bones and muscles, causing chronic joint pain and fatigue.   There is no cure for fibromyalgia and no direct cause is known although certain factors – such as genetics and stress – may act as triggers for the disease.

Reviews in the scientific literature for using cannabis to treat fibromyalgia are mixed. I found only one double-blind, placebo-controlled randomized, controlled trial which used a synthetic form of cannabinoid and concluded that it was a “beneficial, well-tolerated treatment option” that could be a viable adjunct to other therapies.  But other anecdotal studies favored botanical cannabis – in one such study, over half of the participants reported that they were able to stop taking prescription drugs entirely.

Driven to Distraction – Another Way Cannabis Curbs Pain

Relieving hard-to-treat pain, be it neuropathic or central, might result also from an aspect of cannabis consumption that is hidden in plain sight.  When individuals use cannabis, the parts of their brains associated with reward and motivation are more active. In turn, the brain releases more rewards-driven neurotransmitters than usual, releasing a sense of euphoria. Cannabis also typically makes people more easily distracted, because their short-term memory abilities get temporarily compromised. It shouldn’t surprise anyone that boosting mood and creating distraction can bring about pain relief.

Some Practical Considerations

Although cannabis is certainly a promising adjunct to the vast playing field of pain management, some caveats bear mentioning.  Every article I’ve read on cannabis and pain concludes that more research is necessary to determine what particular strains work for specific conditions.   How cannabis is ingested matters too – drops, vapors and edibles behave completely differently from person to person.

And of course we’ll have to figure out how to determine dosage and the proper ratios of the various cannabinoid compounds.   Research writers are quick to warn of adverse side effects and a weakness in efficacy as tolerance develops, especially when using high-THC/low-CBD cannabis strains.

Using cannabis in medicine, especially in pain management, is not without complications but I’m hopeful that we will learn from our past mistakes and resolve to do better – most pointedly from the observed success of decreasing opioid deaths in legalized medical cannabis states.   The slow climb to identifying specific treatment plans for medical cannabis will only come with more trial and error studies as additional researchers chime in.  Sometimes my head hurts from grappling with the learning curve of a treatment laden with possibilities but with so many unanswerable questions at the present moment.   But that’s one pain I’m willing to weather.

Out and about: Shopping at CBD dispensaries – Part One

Recently I’ve been noticing a number of “botanical”/CBD stores springing up in my neck of the woods – mostly in small strip-centers and in modest one-room store fronts.   One such store is nestled in a tiny complex on a busy street that mounts a steep hill just blocks from my house.  It’s easy to miss and I had to drive around the block to find the parking lot.

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Inside I found a tidy shop with shelves of various tinctures, sprays, creams and colorful packages of what looks like gummy candy.  A saleswoman perched on a stool behind the counter.  I told her I was a nurse and was curious about which CBD products were selling the most and for what purposes.  Mostly I just wanted to hang out a bit and chat up the customers myself.

The saleslady was agreeable and she fixed me with her gaze.   She had her own personal story to tell. “My doctor prescribed Valium for me after my husband died last year,” she said.  “Three times a day.  Plus Ambien for sleep.  I thought I was going crazy; the drugs made me feel like a zombie.”

“Then I got this job and learned about CBD.  I weaned off my prescription drugs in about a month.  Now I just take a dropper-full in the morning and in the evenings.  If I’m feeling a bit anxious, I just eat a gummy. “

Various customers float in.  One woman brings in her seven-year-old son who has attention deficit disorder.  A man with a grey ponytail pulls up on a motorcycle to buy a CBD-infused topical cream for his back pain.   A woman in a business suit wants something to help her stay focused at work.

Each customer is invited to sit down and discuss their health goals, then offered a sample of the tincture recommended.  It’s a thoughtful, give and take exchange.  Before they leave, with or without a purchase, each person is given written dosing and usage information with a cursory overview of the endocannabinoid system.

CBD as a Multi-tasker and Receptor Activator

This experience has me musing about how CBD can be so many things to many people.   The scientific literature calls it a “pleiotropic” drug which means that it produces numerous effects through multiple molecular pathways.   Over 65 molecular targets have been identified for CBD.

Unlike its cousin THC, CBD does not activate the body’s CB1 and CB2 receptors. Instead, it activates other receptors, like the adenosine and serotonin receptors – which in turn play parts in regulating various nervous system properties.   Receptors are proteins that sit on cell surfaces and bind chemicals. When they bind a chemical, they create a change, perhaps by opening a channel, or initiating a signal to make a neuron fire more or fire less. What a receptor does depends on its type and also where it’s located in the brain.

How CBD Boosts Endocannabinoids

So how does CBD get inside a human cell to bind to a receptor in the first place? It has to pass through the cell membrane by hopping aboard a fatty acid binding protein (FABP), which accompanies various lipid molecules into the cell’s interior. These transport molecules also escort the brain’s own cannabis molecules, the endocannabinoids, across the membrane to several targets within the cell.

Since CBD has to “compete” with endocannabinoids to bind with these transport proteins, it effectively interferes with the eventual breakdown of endocannabinoids by metabolic enzymes once they land inside a cell.  You could say that it allows endocannabinoids to hang around a little longer in the brain since it delayed passage into the cell interior.   It strikes me that in many ways CBD acts as a “reuptake inhibitor” drug which means that it keeps certain neurotransmitters from being absorbed, mimicking many pharmaceutical drugs.

CBD and Adenosine

One of the important neurotransmitters that CBD affects is adenosine. In the brain adenosine is an inhibitory neurotransmitter, depressing the central nervous system when needed. In normal conditions, it promotes sleep and suppresses arousal.   When you drink a cup of coffee to wake yourself up, the caffeine works by suppressing adenosine.

But adenosine does other things – In the heart adenosine causes dilation of the coronary blood vessels that improves blood circulation.  Adenosine also increases the diameter of blood vessels in the peripheral organs. By delaying the reuptake of this neurotransmitter, CBD boosts adenosine levels in the brain, which regulates adenosine receptor activity.

Inhibiting adenosine uptake activation is one the reasons that CBD works so well for anxiety.  Adenosine receptors are involved in the release of dopamine and glutamate, two neurotransmitters that play major roles in behavioral and cognitive processes. Dopamine is involved in cognition, motor control, motivation and reward mechanisms, while glutamate is one of the major mediators of excitatory signals, being involved in memory, learning and cognition.  One of the drugs we use for managing Alzheimer’s disease, Mamentine, works by inhibiting glutamate.

CBD and Depression – Working on Serotonin

In a similar manner to adenosine, CBD in high concentrations has been shown to activate another receptor called the 5-HT1A serotonin receptor.   5-HT1A is a subtype of the receptor for serotonin, a neurotransmitter well known as a regulator of mood and social behavior, appetite and digestion, sleep, memory, and sexual desire and function.

How do we get more of the feel-good serotonin neuro transmitter onboard?  Anyone who has been treated for depression knows that the usual solution comes in the form of a prescription drug in a class of medications called Selected Serotonin Reuptake Inhibitors ( SSRI’s)  like Prozac and Zoloft. SSRI’s work by blocking reabsorption of serotonin in the brain, increasing the availability of serotonin in the synaptic space.  In turn, brain cells transmit more serotonin signals, which – at least in theory – reduce anxiety and boost mood.

But CBD researchers are suggesting that CBD may boost signaling through serotonin receptors just like SSRI’s. In fact, in one animal study, Spanish researchers found that CBD enhances 5-HT1A transmission and may affect serotonin faster than SSRIs.

Some Conclusions

There’s much more to be said about CBD but here are a couple of conclusions that are jumping out at me right now.

CBD, just one of the many compounds from the cannabis plant, seems to yield similar benefits to current prescriptive drugs without significant side effects.  It has the power to activate as well as to inhibit neurotransmitters selectively – just as some drugs do.  Little wonder that a large-scale survey conducted exactly one year ago reported that over half of CBD-using respondents were able to stop or decrease their prescription medicines.   From where I’m sitting, the most common reasons people buy CBD – depression, anxiety, pain relief and insomnia – are often the most difficult conditions to treat.

Medicine needs to consider how cannabis dispensaries conduct business with their customers, allowing patients to consider options and optimal dosage based on their individual needs and goals.  One size does not fit all.  Everything we ingest to support health – prescription pills from the Walgreens pharmacy, multivitamins from Whole Foods or power smoothies from Jamba Juice – are metabolized differently because our own unique biochemistries.

Taking a Leaf from this Page

Patient-directed goals.  Transparent information.  Complete accessibility.  The ability to adapt a medicine to suit a specific need for a specific person and allowing that person to adjust the dosage as needed.  If only we could see this in conventional healthcare.

In a Bad Way: Pain, Opioids, and Cannabis

Part One

Every summer, I’m invited to speak to a support group for people who live with chronic pain. The group members suffer from various ailments that hurt and are hard to treat – rheumatoid arthritis, fibromyalgia, low back pain.  Some are cancer survivors.  So I’m a bit off -field as a neurology nurse but I talk about how the brain responds to perpetual stress and lack of proper sleep, two subjects with which they are well acquainted.

People who suffer with intractable pain will tell you of all the visits they make to try to get help – visits to pain specialists, to acupuncturists, to chiropractors, to therapists, to the vitamin aisle at Whole Foods.  Oh, and to the pharmacy.  Most will tell you that the narcotic pain drugs that come from a pharmacy – the kind that are ordered on a special triplicate prescription form – are strictly last-resort measures.  So much so, that sometimes they will choose the pain over the drug.  One middle-aged man with chronic head and neck pain told me, “I just live hour to hour.  The pain has moved in and become a part of me.”

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“Pain is what the patient tells you it is” was a mantra I learned back in nursing school. It’s a complicated monster involving both subjective and objective experience. If your knee hurts, it’s not just your knee that bothers you.  It’s your brain relentlessly ruminating over your knee pain and how it might affect you now and how you envision your future self – say, cruising around Walmart in a motorized scooter.

Pain is big and costly.  Approximately, 100 million U.S. adults are encumbered by chronic pain, prompting more than 50 percent of all annual physician visits.  The financial burden of pain-related issues is in excess of $600 billion in annual healthcare costs and lost productivity.

Despite all the hand-wringing and political posturing about the aberrant use of opioids in this country, back here in Dogpatch they still seem to be regarded by many as the best pharmacotherapy for pain relief.  And for the short term, they can work well.  At least we thought we did.  “Get your patient off the pain ceiling” I was advised during my early years as a hospital nurse on an acute surgical floor.  This meant that we administer whatever it takes to get the terrible pain under control, opening the door for the real healing to begin.

But we know now that opioids are lousy for chronic pain.  That’s because over time such drugs make a person both hate and need that next hit and will empty their bank account to get it.  The prevailing theory behind such behavior is called “Opponent Process Theory” and there’s a long, scientific explanation that accompanies it.  The short version is that every drug you take will elicit both positive (such as euphoria) and negative effects (such as headache or nausea) in your body.  The first time you take the drug the positive effects are overwhelming and you feel absolutely terrific.  But as you take the drug more and more, the negative effects start to override the positive effects.  It’s not that you are building a tolerance but you need more of the drug to revisit that first dose experience.  Your body’s neurobiology is confused since the presence of the drug has become the new normal.   The irony is that at this point, drug users can actually become more sensitive to painful stimuli, a condition known as opioid- induced hyperalgesia.

Ouch.

Interestingly, as more states introduce medical and recreational cannabis policies, the learning curve is ramping up about the relationship between cannabis and opioids.   More rigorous studies have begun to appear providing evidence for the correlation of medical cannabis with decreased opioid usage and mortality.  For example, a recent examination of Medicare claims data also showed that the use of prescription pain medications, including opioids, was significantly reduced in states following the implementation of medical cannabis laws.   Another study demonstrated that the percentage of drivers testing positive for opioids after traffic fatalities was significantly reduced in states with medical cannabis laws compared to states without such laws. A University of Michigan March 2016 study published in the Journal of Pain found that cannabis decreased side effects from other medications, improved quality of life and reduced use of opioids by 64 percent.

When you look at studies collectively and a pattern seems to emerge – in this case, that medical cannabis is inversely correlated with opioid usage and mortality – you still need to dig deeper and ask why such a relationship exists.  Did the patients with chronic pain initiate their treatment with cannabis, thus lowering the need for opiates?  Or were opioid drugs used initially followed by a transition to cannabis?  These types of sundry particulars are what I’m most curious about.  The bottom line is finding out what works best for most people – and that’s an answer that will only come with more widespread usage and practice one patient at a time.

As I cruise Pub Med for scientific abstracts on this subject, more practitioners – who live and work in areas of legalized use – are chiming in with their own conundrums.  Here are a few I came across: Should cannabis be treated like alcohol, with established safe/dangerous thresholds?   If so, what is the threshold? If cannabis is an acceptable substitute for opioids, how should it be initiated, and graduated as opioids are tapered down?   When does treatment of pain begin to look like sanctioned cannabis use disorder?

It strikes me that we are now straddling the chasm between the old glory days of opioids and the burgeoning science of medical cannabis, at least in the realm of pain management.  Indeed, cannabis is now being considered in the same way that opioids were decades ago – a drug class of pain-relief enveloped by a huge social movement.   What a long, strange trip we have ahead of us.

Next time (stay tuned) – Part Two:  Different types of pain and how cannabis works to relieve it