Cannabinoids in the management of difficult to treat pain

Cannabinoids in the management of difficult to treat pain – long detailed PubMed article

Abstract: This article reviews recent research on cannabinoid analgesia via the endocannabinoid system and non-receptor mechanisms, as well as randomized clinical trials employing cannabinoids in pain treatment. Tetrahydrocannabinol (THC, Marinol®) and nabilone (Cesamet®) are currently approved in the United States and other countries, but not for pain indications. Other synthetic cannabinoids, such as ajulemic acid, are in development. Crude herbal cannabis remains illegal in most jurisdictions but is also under investigation. Sativex®, a cannabis derived oromucosal spray containing equal proportions of THC (partial CB1 receptor agonist ) and cannabidiol (CBD, a non-euphoriant, anti-inflammatory analgesic with CB1 receptor antagonist and endocannabinoid modulating effects) was approved in Canada in 2005 for treatment of central neuropathic pain in multiple sclerosis, and in 2007 for intractable cancer pain. Numerous randomized clinical trials have demonstrated safety and efficacy for Sativex in central and peripheral neuropathic pain, rheumatoid arthritis and cancer pain.

Cannabinoid analgesics have generally been well tolerated in clinical trials with acceptable adverse event profiles. Their adjunctive addition to the pharmacological armamentarium for treatment of pain shows great promise.

A clinical endocannabinoid deficiency has been postulated to be operative in certain treatment-resistant conditions (Russo 2004), and has received recent support in findings that anandamide levels are reduced over controls in migraineurs (Sarchielli et al 2006), that a subset of fibromyalgia patients reported significant decreased pain after THC treatment (Schley et al 2006), and the active role of the ECS in intestinal pain and motility in irritable bowel syndrome (Massa and Monory 2006) wherein anecdotal efficacy of cannabinoid treatments have also been claimed.

The endocannabinoid system is tonically active in control of pain, as demonstrated by the ability of SR141716A (rimonabant), a CB1 antagonist, to produce hyperalgesia upon administration to mice (Richardson et al 1997). As mentioned above, the ECS is active throughout the neuraxis, including integrative functions in the periacqueductal gray (Walker et al 1999a; Walker et al 1999b), and in the ventroposterolateral nucleus of the thalamus, in which cannabinoids proved to be 10-fold more potent than morphine in wide dynamic range neurons mediating pain (Martin et al 1996). The ECS also mediates central stress-induced analgesia (Hohmann et al 2005), and is active in nociceptive spinal areas (Hohmann et al 1995; Richardson et al 1998a) including mechanisms of wind-up (Strangman and Walker 1999) and N-methyl-D-aspartate (NMDA) receptors (Richardson et al 1998b). It was recently demonstrated that cannabinoid agonists suppress the maintenance of vincristine-induced allodynia through activation of CB1 and CB2 receptors in the spinal cord (Rahn et al 2007). The ECS is also active peripherally (Richardson et al 1998c) where CB1 stimulation reduces pain, inflammation and hyperalgesia. These mechanisms were also proven to include mediation of contact dermatitis via CB1 and CB2 with benefits of THC noted systemically and locally on inflammation and itch (Karsak et al 2007). Recent experiments in mice have even suggested the paramount importance of peripheral over central CB1 receptors in nociception of pain (Agarwal et al 2007)

Cannabinoid agonists produce many effects beyond those mediated directly on receptors, including anti-inflammatory effects and interactions with various other neurotransmitter systems (previously reviewed (Russo 2006a). Briefly stated, THC effects in serotonergic systems are widespread, including its ability to decrease 5-hydroxytryptamine (5-HT) release from platelets (Volfe et al 1985), increase its cerebral production and decrease synaptosomal uptake (Spadone 1991). THC may affect many mechanisms of the trigeminovascular system in migraine (Akerman et al 2003; Akerman et al 2004; Akerman et al 2007; Russo 1998; Russo 2001). Dopaminergic blocking actions of THC (Müller-Vahl et al 1999) may also contribute to analgesic benefits.

The glutamatergic system is integral to development and maintenance of neuropathic pain, and is responsible for generating secondary and tertiary hyperalgesia in migraine and fibromyalgia via NMDA mechanisms (Nicolodi et al 1998). Thus, it is important to note that cannabinoids presynaptically inhibit glutamate release (Shen et al 1996), THC produces 30%–40% reduction in NMDA responses, and THC is a neuroprotective antioxidant (Hampson et al 1998). Additionally, cannabinoids reduce hyperalgesia via inhibition of calcitonin gene-related peptide (Richardson et al 1998a). As for Substance P mechanisms, cannabinoids block capsaicin-induced hyperalgesia (Li et al 1999), and THC will do so at sub-psychoactive doses in experimental animals (Ko and Woods 1999). Among the noteworthy interactions with opiates and the endorphin/enkephalin system, THC has been shown to stimulate beta-endorphin production (Manzanares et al 1998), may allow opiate sparing in clinical application (Cichewicz et al 1999), prevents development of tolerance to and withdrawal from opiates (Cichewicz and Welch 2003), and rekindles opiate analgesia after a prior dosage has worn off (Cichewicz and McCarthy 2003). These are all promising attributes for an adjunctive agent in treatment of clinical chronic pain states.

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3 thoughts on “Cannabinoids in the management of difficult to treat pain

    1. Zyp Czyk Post author

      Hello Lisa – It sounds like you are not in a state that allows medical marijuana, but that will probably change over the next years as this country becomes more advanced in their drug policies. The DEA is operating on assumptions that have been scientifically disproven, yet states its intentions to continue enforcing outdated rules. This is incredibly frustrating! (See “DEA position on Cannabis” at https://edsinfo.wordpress.com/2013/12/08/dea-position-on-cannabis/)

      I want you to know though, that pain clinics are often not the best source of pain management. Many are far too invested in selling their interventional procedures (See “Pain Management: Surgery but Not Opiates” at
      https://edsinfo.wordpress.com/2014/02/01/pain-management-surgery-but-not-opiates/) and others are more concerned about preventing addiction than providing pain relief. My experiences have been terrible: they didn’t believe in my pain because it was still undiagnosed and their first priority was to take away the opiates I’d already been taking for years.

      When I was told I was “making up my own pain” just to get opiates, I got depressed and suicidal, thinking I’d have to live in excruciating pain the rest of my life. An addiction counselor eventually verified that I was not an addict, just a person in pain, and strongly urged me to search for a better doctor.

      I finally received compassionate pain management from “regular” doctors: first a neurologist and now an internist (my primary care doc). After having tried everything else, these individuals were willing to prescribe me opiates in the amount I need to make my pain bearable. I help them out by keeping a detailed pain, activity, and medication diary that I discuss with them at my appointments.

      They understand that pain relief requires a multi-faceted approach, including a healthy diet, exercise, and other non-opiate medications. For me, cannabis is an adjunct therapy, just like the SNRI’s, mood stabilizers, and hormones I also take.

      Perhaps you could find another doctor willing to help you through this – you never know until you ask. I didn’t even know my PCP could prescribe opiates until I mentioned to her that the other doctor I was having so much trouble with didn’t want me to take them.

      I encourage you to keep looking and not give up as I almost did.

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      Reply
  1. Pingback: CLEAR Daily News 1st May 2014

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