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CME / ABIM MOC / CE

What Is the CBD Dosing Required for Effective Pain Relief?

  • Authors: News Author: Damian McNamara; CME Author: Laurie Barclay, MD
  • CME / ABIM MOC / CE Released: 12/14/2018
  • THIS ACTIVITY HAS EXPIRED
  • Valid for credit through: 12/14/2019
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Target Audience and Goal Statement

This article is intended for primary care physicians, neurologists, nurses, pathology and laboratory medicine practitioners, pharmacists, psychiatrists, and other members of the healthcare team who treat and manage patients considering cannabidiol (CBD) treatment for relief of pain and/or anxiety.

The goal of this activity is to provide medical news to primary care clinicians and other healthcare professionals in order to enhance patient care.

Upon completion of this activity, participants will be able to:

  • Describe the effects of acute and repeated CBD administration on neurotransmission, pain, and anxiety-like behaviors, according to rat models
  • Determine potential clinical implications of the effects in rat models of acute and repeated CBD administration on neurotransmission, pain, and anxiety-like behaviors
  • Outline implication for the healthcare team


News Author

  • Damian McNamara

    Freelance writer, Medscape

    Disclosures

    Disclosure: Damian McNamara has disclosed no relevant financial relationships.

CME Author

  • Laurie Barclay, MD

    Freelance writer and reviewer, Medscape, LLC

    Disclosures

    Disclosure: Laurie Barclay, MD, has disclosed the following relevant financial relationships:
    Owns stock, stock options, or bonds from: Pfizer

Editor

  • Esther Nyarko, Pharm

    Associate CME Clinical Director, Medscape, LLC

    Disclosures

    Disclosure: Esther Nyarko, PharmD, has disclosed no relevant financial relationships.

CME Reviewer/Nurse Planner

  • Amy Bernard, MS, BSN, RN-BC, CHCP

    Lead Nurse Planner, Medscape, LLC

    Disclosures

    Disclosure: Amy Bernard, MS, BSN, RN-BC, CHCP, has disclosed no relevant financial relationships.


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CME / ABIM MOC / CE

What Is the CBD Dosing Required for Effective Pain Relief?

Authors: News Author: Damian McNamara; CME Author: Laurie Barclay, MDFaculty and Disclosures
THIS ACTIVITY HAS EXPIRED

CME / ABIM MOC / CE Released: 12/14/2018

Valid for credit through: 12/14/2019

processing....

Clinical Context

The effects of cannabis in humans include euphoria, increased sensitivity to external experience, relaxation, and potential for addiction. Cannabidiol is a compound in the cannabis plant that lacks euphoric and addictive qualities and that may be useful to treat conditions including chronic pain, nausea, epilepsy, psychosis, and anxiety. The optimal therapeutic dose of CBD has not yet been determined, and it has been used in a wide dose range from 2.85 to 50 mg/kg/day.

The therapeutic effects of CBD appear to emanate from its interaction with the serotonin (5-HT) 1A receptor, but its effects on 5-HT neuronal activity and in models of neuropathic pain were previously unknown. The goals of this study by De Gregorio and colleagues were to explore the effects of acute CBD administration on modulation of dorsal raphe nucleus (DRN) 5-HT neuronal activity in naive animals and to evaluate the effect of repeated low-dose CBD treatment on mechanical allodynia, anxiety-like behaviors, and DRN 5-HT neuronal activity in the spared nerve injury model of neuropathic pain in rats.

Study Synopsis and Perspective

Repeated administration of CBD is needed to reduce neuropathic pain and related anxiety, new research suggests.

In a study designed to evaluate the dose, treatment duration, and mechanism of action of CBD, the drug modulated nociception, decreased anxiety-like behavior, and increased serotonin activity in a rodent model of neuropathic pain.

CBD also acted on some specific receptors but not others, a finding that paves the way for future therapeutics according to this active component of cannabis.

"These results are clinically relevant, as CBD is known to exhibit few side effects and supports the initiation of clinical trials testing the efficacy of CBD-based compounds for treating neuropathic pain and comorbid mood disorders," the investigators wrote.

One-time acute treatment is likely insufficient.

"The most effective neuropathic pain relief occurs after 1 week of daily CBD treatment," senior author Gabriella Gobbi, MD, PhD, professor of psychiatry, neurobiological psychiatry unit, McGill University, Montreal, Canada, told Medscape Medical News.

Using in vivo electrophysiology, these experiments demonstrated that CBD decreases serotonin firing after an acute injection; however, after one week of treatment, the firing of serotonin increased through the desensitization of the 5-HT1A receptor.

This is the same mechanism observed for selective serotonin reuptake inhibitors (SSRIs), which "also require a few days or weeks before having a therapeutic effect -- likely because some neuroplastic event occurs at the level of the receptors," Dr Gobbi said.

"Translating this to a clinical setting, these results suggest that the best treatment with cannabidiol will be a chronic treatment, but further clinical studies have to confirm this," she added.

The findings were published online in Pain.[1]

Growing Research Interest

Research interest in CBD, a noneuphoric and nonaddictive cannabis component, is growing. Investigators are assessing a wide range of potential indications,[2] including treatment of chronic pain, nausea, psychosis, and anxiety, as well as epilepsy.

In addition, in June, the US Food and Drug Administration (FDA) approved a purified formulation of CBD (Epidiolex ® oral solution, GW Pharmaceuticals) to treat 2 rare forms of epilepsy.

The current study is not the only one to evaluate CBD for the treatment of neuropathic pain. Previous researchers assessed CBD alone[3] or in combination[4] with tetrahydrocannabinol for this indication; however, few studies have explored the effect of CBD on 5-HT neurotransmission in the DRN, Dr Gobbi and colleagues wrote. This region of the brain is important because it is involved in both mood disorders and pain, they noted.

The investigators studied 229 adult male Wistar rats. They assessed the effects of both acute CBD therapy and repeated low-dose CBD on neuropathic pain modulation and responses.

Through a series of tests, they studied the firing activity of neurons, nerve desensitization, and reactions to mechanical allodynia. They also evaluated behavior using an open field test, a forced swim test, an elevated plus maze test, and a novelty-suppressed feeding test.

Electrophysiologic recordings demonstrated that neuropathic pain provoked a maladaptation of 5-HT neurotransmission. This action, in turn, caused a decrease in the firing activity of spontaneously active DRN 5-HT neurons.

Effective Doses

The investigators also sought clarity on an effective dose of CBD. CBD has been used therapeutically in doses ranging from 2.85 to 50 mg/kg/day, "meaning that its therapeutic dose is still unclear," the researchers noted.

For acute treatment, they administered cumulative injections of 0.05 to 0.25 mg/kg of CBD and 10 to 50 µg/kg of D-lysergic diethylamide acid (LSD). They also administered a single injection of the 5-HT1A antagonist WAY 100635, the AM 251, and/or the transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine.

By pretreating with these antagonists and then administering CBD, the investigators demonstrated that the 5-HT1A and TRPV1 receptors are involved in the agent's mechanism of action and ruled out involvement of the CB1 receptor.

Repeated treatment showed that the lowest IV CBD dose needed to cause a significant decrease in 5-HT neuronal activity was 0.10 mg/kg. The difference was significant compared with vehicle preinjection in Bonferroni post hoc analyses (n=9; P <.05).

In addition, a 0.25-mg/kg dose of CBD "completely shut down neuronal activity" (n=9 ; P <.001), the researchers reported.

Using the spared nerve injury model of neuropathic pain, "we found that repeated CBD treatment was able to prevent mechanical allodynia and anxiety-like behavior in rats experiencing neuropathic pain, but through different mechanisms," they wrote.

The investigators noted that TRPV1 channels were required for the antiallodynic but not the anxiolytic effects of CBD. In contrast, 5-HT1A receptors were required for the anxiolytic and, to a lesser extent, the antiallodynic effects of CBD.

These receptors are essential because multiple studies have demonstrated "that the 5-HT1A receptor is crucial for the mechanism of anxiety and depression relief," Dr Gobbi said.

"Very Surprising" Results

Dr Gobbi noted that in the past 15 years, investigators have conducted many preclinical studies with THC, CB1 agonists, and fatty acid amide hydrolase inhibitors or endocannabinoid enhancers; however, "it was very surprising to see that CBD has a mechanism of action that is different from its 'cousin' drugs."

The preclinical findings of this research support future clinical trials, Dr Gobbi added.

"These animal studies suggest the indication for CBD use in humans' neuropathic pain and comorbid anxiety," Dr Gobbi said. "We have a better idea about the doses in humans, [because] the FDA has conversion tables to translate doses from animals to humans, and... we know more about the length of treatment."

Could the findings have new implications, given recent government approvals for use of cannabis? "I hope so," she answered.

"Canada has legalized recreational cannabis and made medicinal cannabis more accessible, but little is yet known about medical cannabis. A lot of patients are using mixtures of THC [and] CBD without knowing the appropriate indications, doses, side effects, and interactions with other drugs," Dr Gobbi noted.

"This research -- I hope -- will encourage more systematic medical cannabis research to help patients and doctors to make more evidence-based choices," she said.

Caution Urged

Commenting on the findings for Medscape Medical News, Yasmin Hurd, PhD, professor of neuroscience, psychiatry, and pharmacologic sciences, Icahn School of Medicine at Mount Sinai, New York, New York, said this is an interesting study "that provides strong preclinical findings in support of the antinociception and antianxiety effects of CBD relevant to the condition of neuropathic pain."

Dr Hurd added that she applauds the investigators' use of multiple approaches -- behavioral, pharmacologic, and electrophysical measurement of cell firing -- because this strengthened the overall findings. She also said the research strategy provided insights about the different biological mechanisms associated with CBD's analgesic and anxiolytic properties.

"Clinical trials are of course still necessary, but the findings suggest that CBD may be potentially beneficial as a future treatment in reducing chronic pain and anxiety, which are often comorbid in neuropathic pain and related conditions," she said.

Dr Hurd, who was not affiliated with this study, has authored a review article on the potential role of marijuana as an alternative to opioids for the treatment of addiction.[5]

When also asked by Medscape Medical News to comment on the study, Joshua Aviram, PhC, faculty of social welfare and health sciences, University of Haifa, Israel, was less enthusiastic.

"Although mechanistic observations on animal models are critical to the understanding of phytocannabinoids activity, human chronic pain is much more complicated than the mere nociception process," Mr Aviram said.

"Until these findings can be substantiated in high-quality controlled trials or even cohort studies on chronic pain patients, no responsible clinical implications can be drawn from these findings on CBD activity," he added.

Mr Aviram, principal investigator of a systematic review and meta-analysis on the efficacy of cannabis-based medicines for pain management,[6] was not affiliated with the current study.

The study was supported by a matching grant from the Ministere de l'Economie Science et Innovation du Quebec and Aurora Cannabis Inc. Dr Gobbi, Dr Hurd, and Mr Aviram have disclosed no relevant financial relationships.

Study Highlights

  • In a rat model, single-unit extracellular recordings showed that acute intravenous (IV) increasing doses of CBD (0.1-1.0 mg/kg) decreased the firing rate of 5-HT neurons in the DRN, which is implicated in mood disorders and in pain.
  • A CBD dose of 0.25-mg/kg completely stopped firing of 5-HT neurons (P <.001).
  • This response was prevented by IV administration of the 5-HT1A antagonist WAY 100635 (0.3 mg/kg) and the TRPV1 antagonist capsazepine (1 mg/kg) but not by the CB1 receptor antagonist AM 251 (1 mg/kg).
  • Repeated subcutaneous (SC) CBD administration (5 mg/kg/day for 7 days) increased 5-HT firing by desensitizing 5-HT1A autoreceptors.
  • Rats subjected to the spared nerve injury model for 24 days had reduced 5-HT firing activity and mechanical allodynia: triggering of a pain response from stimuli that are not normally painful.
  • These rats also had increased anxiety-like behavior in the elevated plus maze test, open-field test, and novelty-suppressed feeding test.
  • After treatment with CBD for 7 days, these rats exhibited decreased mechanical allodynia and anxiety-like behavior, as well as normalization of 5-HT activity.
  • Capsazepine (10 mg/kg/day SC for 7 days) fully prevented the effects of CBD on reducing allodynia, which were also partially prevented by WAY 100635 (2 mg/kg/day SC for 7 days).
  • Only WAY was able to block the anxiolytic effect of CBD.
  • According to their findings, the investigators concluded that CBD modulated serotonergic transmission and reversed allodynia and anxiety-like behavior in a rat model of neuropathic pain.
  • An acute injection of CBD reduced serotonin firing, but one week of repeated CBD treatment increased serotonin firing via desensitization of the 5-HT1A receptor.
  • Repeated low-dose CBD treatment induced analgesia mainly through TRPV1 activation, lowered anxiety through 5-HT1A receptor activation, and normalized impaired 5-HT neurotransmission under neuropathic pain conditions.
  • Previous research has also highlighted the role of the 5-HT1A receptor in relief of anxiety and depression.
  • The findings suggest that repeated CBD administration for at least one week is needed to reduce neuropathic pain and associated anxiety, as a single acute treatment is unlikely to be effective.
  • This time course of response is similar to that seen with SSRIs, for which a therapeutic response occurs only after several days or weeks, most likely caused by neuroplastic changes at the receptor level.
  • Understanding the selective activity of CBD on certain specific receptors may be useful for future development of new analgesic and anxiolytic compounds.
  • Given the good tolerability and side effect profile of CBD, the findings substantiated initiation of clinical trials to test CBD and CBD-based compounds for relief of neuropathic pain and associated mood disorders.
  • Nonetheless, results of an animal model study cannot be directly extrapolated to a clinical setting, and further clinical studies are needed to confirm the efficacy of chronic CBD treatment.
  • Potential indications for CBD include treatment of chronic pain, nausea, psychosis, anxiety, and seizure disorders.
  • In June, the US Food and Drug Administration approved a purified oral CBD formulation for treatment of 2 rare types of epilepsy.
  • Although some governments have legalized recreational cannabis and liberalized use of medical cannabis, the cannabis plant contains varying mixtures of THC and CBD.
  • Research such as the present study is needed to determine appropriate indications, dosage, adverse effects, and drug interactions for CBD and other compounds contained in cannabis.

Clinical Implications

.

  • CBD modulated serotonergic transmission and reversed allodynia and anxiety-like behavior in a rat model of neuropathic pain.
  • The findings suggest that repeated CBD administration for at least one week is needed to reduce neuropathic pain and associated anxiety, as a single acute treatment is unlikely to be effective.
  • Implications for the Healthcare Team: Potential indications for CBD include treatment of chronic pain, nausea, psychosis, anxiety, and seizure disorders, but further clinical studies are needed to confirm the efficacy of chronic CBD treatment and the need for repeated dosing.
  • The role of the healthcare team member is to continue to enhance their own knowledge through seeking up to date evidence, guide and support patients to improve outcomes, in collaboration with other members of the healthcare team. 

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