2017 needs to be the year we fight back against the opioid epidemic. We will use the greatest weapon—cannabis.

Is this wishful thinking? Is there scientific justification to this speculation?

My wife is a resident physician in Seattle’s trendy Capitol Hill neighborhood. Early in her residency, she was musing with her colleagues over their challenging patient interactions. I chimed in, “How many of your patients are just after pain medication?” One of the residents looked down and shook his head. “Too many. And if we don’t give [opioids] to them, they just keep switching their doctor until they find someone who will.”

And those are the high functioning opioid abusers. Dirty needles on the sidewalk or in empty green spaces off Seattle’s web of multi-use trails are mere shadows of those that have spiraled to heroin.

The opioid epidemic is being propelled by the pharmaceutical industry to seemingly irredeemable heights, with 650,000 opioid prescriptions dispensed daily in the U.S., enough to give nearly every American their own bottle of pills each year.

It’s killing us. Of the 55,000 lethal drug overdoses each year, 20,000 were related to prescription opioids, and another 13,000 due to heroin. Over 60 percent of these deaths were deemed accidental, highlighting the loss of control experienced with opioid addiction.

So why take opioids in the first place?

Because if you’re in pain, they work. Evidence for their medicinal use stretches back to the Ebers Papyrus in 1500 BCE. The problem clearly isn’t in their efficacy, it’s in their substantial risk for abuse and dependence. For proof, there’s no need to look further than the two million Americans who have a substance use disorder involving opioid-based prescription pain medications.

And talk about a “gateway drug!” A generation of D.A.R.E. graduate millennials will forever associate this term with marijuana, despite a dearth of evidence. But four-out-of-five heroin users started with a doctor’s prescription for FDA-approved pain meds. So to combat the opioid epidemic, one strategy is to reduce the need for high levels of opioid-based pain treatments.

That won’t be easy. Chronic pain (defined as pain lasting longer than three months) is one of the greatest hardships in the developing world. Some estimates even claim that it affects 30 percent of Americans. Currently, the most effective tool in the physician’s arsenal is treatment with opioids (for example: OxyContin, Percocet, Vicodin, and Fentanyl). In some cases, they should be used. After all, nothing combats pain like a good opioid treatment!

But without close monitoring, and repeated use, tolerance to the drug can develop. With tolerance, higher quantities and more frequent use is required to achieve pain relief. More prescriptions are filled, more pills consumed.

Is there a way to reduce the need to take so many opioids for pain relief?

The research suggests there is. There’s mounting evidence that cannabis may be an effective means of long-term pain relief when used in conjunction with small amounts of opioid-based pain killers. How can this be? Opioids work on the body’s opioid receptors, while cannabis works largely on the body’s cannabinoid receptors. Could it be that together, their effect is greater than the sum of their parts?

It’s important to recognize that pain is a subjective feeling.

There are no pain receptors in the brain, that when activated, give the sensation of pain. Instead, pain results from a complex interaction of incoming signals from the periphery (e.g., shoulder inflammation) with a host of cognitive factors (e.g., attention to the injury), context factors (e.g., expectation of pain), mood factors (e.g., depressed or anxious state), chemical factors (e.g., opioid system function) and genetic factors (e.g., predisposition to weaker endogenous opioid signaling).

Opioid pain medications are powerful drugs because they work to reduce pain at multiple levels. First, they can block incoming signaling from the periphery to the brain. The strength of the signals from your sore shoulder are weakened by activation of opioid receptors as they enter the spinal cord in their journey up to your brain. Weaker signals, less pain. This is known as ascending pain modulation, and opioids are really good at dampening pain signals.

Opioids also increase dopamine signaling in reward centers in your brain, thereby increasing your mood and further reducing subjective pain. You don’t need science to tell you that when you feel good, you experience less pain. But it’s not just due to actions in the brain. Your brain actively sends signals back down the spinal cord to modulate the incoming pain signals. These signals from the brain to the spinal cord work to reduce the strength of the incoming signals as they enter the spinal cord. The combination of ascending pain modulation (i.e., from the spinal cord to the brain) and descending pain modulation (i.e., from the brain to the spinal cord) can act to gate the perception of pain.

Like opioids, the endogenous cannabinoid system can similarly reduce pain.

Activating CB1 receptors in the brainstem region called the rostroventral medulla reduces pain through descending pain modulation. However, with pain caused by persistent inflammation, there’s a reduction in the number of CB1 receptors and an increase in CB2 receptors. Activating CB2 receptors in the rostroventral medulla reduces signaling by the inhibitory neurotransmitter, GABA, thereby freeing up the descending pain modulatory signals to reduce pain. So as pain matures from acute to chronic pain, relevant cannabinoid signaling shifts from acting through CB1 receptors to CB2 receptors.

Cannabinoids also have the power to increase dopamine signaling in the brain’s reward centers. Since chronic pain is associated with reduced dopamine signaling in the brain’s reward centers, increasing cannabinoid receptor activity in these regions can improve emotional elements related to the subjective pain experience. Together, and similar to opioids, cannabinoids can modulate pain through ascending and descending pain modulation, as well as modulating emotional elements relating to subjective pain.

So what’s the problem? Why not just smoke a lot of weed or pop a bunch of pills to quell the pain? You could try, and it would be effective… at first. The problem is tolerance.

Both opioid and cannabinoid receptors go through similar changes when activated. Activation of the receptors begins with binding of the neurotransmitter or exogenous drug (e.g., morphine for opioid receptors; THC for cannabinoid receptors) to the receptor. This initiates a series of molecular events inside the neuron that impact neurotransmitter release and provide the intended effect on pain and mood. But if the receptors are activated too frequently, as in the case with repeated pill popping or prolonged THC exposure, the molecular machinery inside the neuron puts a phosphate group on the receptors. This phosphate group prevents the receptor from functioning, and eventually, flags it to be removed from the cell’s membrane, internalized and destroyed.

Tolerance develops as the number of functioning receptors decreases. If you’ve felt the need to increase the number of hits in order to achieve your desired high, you’ve experienced tolerance.

With opioids, it’s particularly problematic. Withdrawal from prescription pain killers can be miserable, and opioid users who have experienced tolerance to their drugs must take increasing amounts just to prevent withdrawal. What began as opioid use intended to reduce pain and achieve a euphoric high eventually shifts towards pill popping just to relieve the symptoms of withdrawal. This level of dependence seeds addiction, which is fed by one prescription after the next until their supply is cut off by doctors or prohibitive cost. By this point, heroin feels like the most reasonable option. If only tolerance to the drug could be prevented in the first place.

Where does cannabis fit into this prescription pain killer story?

It would appear that we’re dealing with two vastly different drugs that act on independent targets. Turns out, the endogenous opioid system and cannabinoid system aren’t entirely independent. In fact, there’s evidence that they directly interact at the molecular level, which lead to behavioral consequences. Take for instance, the anxiolytic effect of low amounts of THC. In mice, a small amount of THC increases the amount of time a mouse spends in the anxiety-provoking illuminated half of a behavioral chamber. Blocking opioid receptors prevents the mice from venturing to the illuminated side of the chamber, thus obstructing THC’s anxiolytic effect.

The link between opioid and cannabinoid signaling also applies to pain.

In a seminal study, researchers found that co-administration of THC and opioids had a synergistic effect on pain relief. That is, the effect of the two drugs in combination was greater than the sum of their individual effects on pain relief.

The researchers first tested the effect of twice-daily THC or morphine injections on a paw-pressure pain test in rats. Initially, THC and morphine, alone, increased the amount of pressure the researchers could provide before the rat withdrew their paw, a measure of pain reduction. However, within a couple of days, the rats experienced tolerance, and neither the THC or morphine injections reduced pain. This coincided with a reduced number of functioning CB1 receptors (in the case of THC injections) or opioid receptors (in the case of morphine injections) in the spinal cord, important in the ascending pain pathway, and a brainstem region called the periaqueductal gray, important in the descending pain modulatory pathway. Reduced CB1 and opioid receptors in these areas led to tolerance and the ineffectiveness of the drugs after a few days.

Then, the researchers took a fascinating step further. They co-administered THC and morphine at substantially lower doses than those used to reduce pain on their own.

Morphine was administered at eight percent of the efficacious dose when used independently, and THC was administered at 20 percent of the efficacious dose. This combination led to substantial pain relief without inducing tolerance. And indeed, the combination of THC and morphine had no impact on the number of functioning CB1 and opioid receptors in the spinal cord or periaqueductal gray.

This is a critical finding.

Essentially, it proposes that one strategy to relieve pain and combat tolerance is by taking low doses of THC-rich cannabis in combination with low doses of opioids. On their own, they’re ineffective at these low concentrations, but in combination, they can be a potent tool for pain relief. And notably, by preventing tolerance from building, this strategy could cut one’s risk of spiraling towards addiction.

So where to go from here?

The opioid pharmaceutical industry is worth nearly $10 billion in sales in the U.S. alone, and you can guarantee that their powerful pharmaceutical lobby isn’t going to simply role over and quit. Why would they? Not only are they making money on the drug sales themselves, but there’s money to be made in treating opioid addiction (estimated at $1.4 billion), overdoses (estimated at $1.3 billion),and its side effects (estimated between $1.9 and $4.8 billion). Instead, research can provide the necessary ammunition.

What we have now is a starting point, but it’s not enough. We need more detailed assessments in rodent pre-clinical models for different types of pain, and we need to extend these studies to human clinical trials.

Most will welcome a new treatment strategy. Physicians are desperate for a more efficacious and safer long-term solution to treat their patients, and government officials (those who aren’t in the opioid-lobby’s pocket) are desperately seeking a solution to the $53.4 billion/year social cost of opioid abuse in this country.

Public perception needs to shift, and research will help.

Opioids are still largely considered safe since they’re prescribed by a doctor and are dispensed by a pharmacist in a white coat. Unfortunately, cannabis is still widely associated with illegality and comes with the social stigma engendered by decades of false propaganda. Cannabis’ prohibition has not only led to significant social costs, but through research and access restrictions, inadvertently led to increased suffering.

But with the recent ballot initiatives passed in a number of states, the acceptance of cannabis is vastly increasing. This increased momentum, as we begin 2017, may provide the fuel by which cannabis rescues us from the opioid epidemic.

For all of HIGH TIMES’ medical marijuana coverage, click here.

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