Targeting Pain Nerves Outside the Brain Could Make Cannabinoid Pain Drugs Practical | Research

The takeaway

A review of peripherally restricted cannabinoids found that targeting cannabinoid receptors on pain-sensing nerves outside the brain could provide pain relief without psychoactive effects, tolerance, or dependence.

Read this if you have chronic pain and are interested in cannabinoid pain treatments without the high.

Peripheral targeting avoids psychoactive effects, tolerance, and dependence

What the researchers found

This review examined strategies to use cannabinoids for pain treatment while avoiding central nervous system effects. Cannabinoid receptors (CB1 and CB2) are abundant on peripheral pain-sensing nerves, and activating them locally can reduce pain signaling.

Several approaches were discussed: using cannabinoid compounds that cannot cross the blood-brain barrier, developing CB2-selective agonists (since CB2 is less prevalent in the brain), and local delivery of cannabinoids directly to painful tissues.

The review noted that peripheral cannabinoid approaches could be particularly beneficial for conditions with prominent peripheral mechanisms, such as diabetic neuropathy and chemotherapy-induced neuropathy, where peripheral nerve damage drives pain.

Why it matters

The main barriers to cannabinoid pain medication are psychoactive effects and dependence potential. If cannabinoids can be restricted to peripheral nerves, these barriers could be eliminated while retaining pain-relieving activity.

The numbers in context

23 states had legalized medical marijuana at the time; conditions highlighted: diabetic neuropathy, chemotherapy-induced neuropathy; strategies: blood-brain barrier exclusion, CB2 selectivity, local delivery

How the study worked

Narrative review of scientific evidence for peripheral cannabinoid system targeting, examining available literature on strategies to achieve pain relief without CNS effects.

What this study cannot tell us

Most peripheral cannabinoid approaches were in preclinical stages. Blood-brain barrier exclusion is difficult to achieve perfectly. Some pain conditions involve central sensitization that peripheral approaches alone may not address.

How to read the evidence

Comprehensive review of a promising therapeutic strategy, though most evidence was preclinical at the time.

When this study was published

Published in 2015. Development of peripherally restricted cannabinoid analgesics has continued.

The bigger picture

The opioid crisis has created urgent demand for non-addictive pain medications. Peripherally restricted cannabinoids represent a promising class of analgesics that could fill this need without the abuse potential of opioids or centrally-acting cannabinoids.

Questions still open

Can peripherally restricted cannabinoids provide sufficient pain relief for severe pain? Will local cannabinoid delivery be practical for chronic conditions? How do peripheral cannabinoid analgesics compare to existing pain medications?

Common questions

Can you get pain relief from cannabinoids without getting high?

This review described several strategies to achieve this: using cannabinoids that cannot enter the brain, targeting CB2 receptors instead of CB1, or delivering cannabinoids locally to painful tissues. These approaches showed promise in preclinical research.

Would these work for nerve pain?

The review highlighted diabetic neuropathy and chemotherapy-induced neuropathy as particularly suitable conditions because the pain originates from peripheral nerve damage, where cannabinoid receptors are abundant and locally targeted treatment could be effective.

Read the original research

Peripherally Restricted Cannabinoids for the Treatment of Pain.

Pharmacotherapy, 35(10), 917-25

View on PubMed ↗Publisher’s paper ↗

Citation

Romero-Sandoval, E Alfonso; Asbill, Scott; Paige, Candler A; Byrd-Glover, Kiara. (2015). Peripherally Restricted Cannabinoids for the Treatment of Pain.. Pharmacotherapy, 35(10), 917-25. https://doi.org/10.1002/phar.1642