Trigeminal neuralgia (TN) is one of the most painful disorders known and may be second only to cluster headaches in degree of pain it produces. Like cluster headaches, trigeminal neuralgia is also known by many as the suicide disease. When describing someone suffering a TN attack, the chairman of Oregon Health & Science University School of Medicine’s department of neurological surgery, Kim Burchiel, M.D., said: “They are begging to be killed.” The trigeminal nerve is responsible for the transmission of all sensory information from the face and head. This includes temperature, pain, and tactile/pressure sensation. Most of us are familiar with the luxury of a functional trigeminal nerve, being pinched on the cheek hurts but the pain is bearable and fades quickly, soft touches are sensuous, and wind on one’s face can be quite the invigorating experience. If this nerve bundle becomes irritated or damaged it can begin to malfunction in the most extreme way. The invigorating wind and sensuous touch can become the trigger for severe sensations of searing, slicing, stabbing, lacerating pain in the mouth, teeth, eye, cheek and ear lasting from a few minutes to several hours. Usually only one side of the face is afflicted though rarely TN can occur bilaterally (1).
There are several ways in which the trigeminal nerve can become irritated and/or damaged through direct assault or more passive demyelination. The most common cause is believed to be vascular compression of the nerve bundle close to where it enervates with the brain stem. This pressure irritates the nerve interfering with its ability to function properly. Eventually the irritation results in demyelination and severe neural dysfunction. The dysfunctional nerve now fires erratically, becomes hypersensitive, and may no long be able to terminate a sensation once the corresponding stimulus has been removed. As a result, someone suffering from this condition will experience paroxysmal allodynia, the sudden onset of extreme pain initiated by non-painful stimuli such as a feather brushing the cheek. Other suspected causes include pressure from tumor, cystic spider bite in the right location, damage from multiple sclerosis, car accident, facial surgery or even body piercing (1).
With no cure and few “successful” treatments for this disorder, it presents the medical community with a difficult therapeutic challenge. Even with the available drugs, surgery to remove the source of irritation or to damage the nerve’s ability to transmit pain and use of gamma radiation to damage the nerve and prevent pain transmission, some estimates say nearly 50 per cent of those affected are unable to obtain substantial relief in the long term (2). Some skilled surgeons and radiologists report 80-90 per cent “success rate” for the latter two treatments. Even so, after surgery and gamma knife treatments the pain can return for some within a few years. Such physiological interventions also come with their own risks such as paralysis of the face and not all patients are willing to face such risks without assurance of success (1).
In general, neuropathic pain conditions such as TN have proven resistant to conventional pain management methods such as treatment with opiates. One class of drug, however, stands out in the research as relatively effective in the management of pain related neuropathy, those which interact with the endocannabinoid system (3). This trend in the research lead Liang, Huang and Hsu, 2004, to propose the endocannabinoid system as a target for methods aimed at treating TN. Next they developed an animal model of TN using rats. In the animal model, neuronal injury is produced by artificial constriction chronically applied to part of the rat’s trigeminal nerve. Rats which underwent a sham surgery but received no constriction of the nerve behaved normally. Rats which received the full experimental procedure expressed signs of hyperresponsiveness, hyperalgesia (extreme reaction to painful stimuli), and allodynia (reaction of severe pain to non-painful stimuli) as do patients with TN. Liang, Huang and Hsu then tested how synthetic cannabinoids WIN 55,212-2 and HU 210 effected the expression of the TN-like behavior in the experimental rats. The doses of these cannabinoids used in this study did not significantly effect the ability of the rats to perform in a test of motor skills (degree of motor skill impairment is believed to be indicative of degree of intoxication). In 2007, Liang, Huang, Hsu published their results. Rats treated with either WIN (WIN 55,212-2) or HU 210 demonstrated significant dose-dependant reductions in hypersensitive behavior, and significant dose-dependant increases in tolerance to thermal or painful stimuli. Blocking the CB1 receptor antagonized the effect of the cannabinoid treatment. However, the effect was not altered by blockade of either the CB2 receptors or the vanilloid 1 receptors. Furthermore, the chronically constricted rat nerves were found to increase production the CB1 receptors over time following surgery. This lead Liang, Huang and Hsu to suggest therapies targeting CB1 receptor activation may prove to be a valuable tool in the treatment of TN (4).
Although the study by Liang, Huang and Hsu (2007) was the first to speak so directly to the use of cannabinoids in the treatment of TN, there are several other studies of neuralgia as well as anecdotal evidence from sufferers of TN indicating they are on to something.
Neuropathic Pain and WIN 55,212-2
Neuralgia and neuropathic pain are synonyms and therefore interchangeable, however, trigeminal neuralgia is not necessarily synonymous with all neuropathic pain. That said, I have tried to present here some of the studies which are most relevant to the topic of trigeminal neuralgia. To start with, one might wonder how effective are cannabinoids at treating neuropathic allodynia, like that seen in TN, when compared to opiates? This question was addressed by Rahn, Makriyannis and Hohmann in 2007. They found in a rat model of vaccine-induced allodynia that not only was the synthetic cannabinoid WIN able to attenuate the expression of allodynia in vaccine-treated rats but that is was also able to do so at doses which were 75 to 80 per cent smaller than that required for morphine to produce the same level of attenuation. This suggests that WIN is 4 or 5 times more potent than morphine at treating this kind of pain (5). TN also produces hyperalgesia and another study found that WIN administered directly to the site of neural injury at a non-systemically active dose, dose-dependently suppressed hyperalgesia as evidenced by reduced hypersensitivity. This effect was found to be CB1 and CB2 dependant only for acute administration of WIN whereas chronic administration of WIN appeared to be antihyperalgesic via the CB1 receptor only (6).
Although the last study indicated that only local activation of the CB1 receptors in the periphery was required for WIN to decrease some neuropathic pain, another study suggests that the ability of WIN to reduce the sensation of neuralgia may have roots in the central nervous system (CNS) as well. In this case, WIN was found to effectively ameliorate both allodynia and hyperalgesia in rats with neuralgia inducing spinal injury. HU 210 and CP 55,940 were only tested on hyperalgesia but were both effective. WIN was further tested by administration either locally in the paw that was used for tests of hyperalgesia or to the CNS both with co-administration for a CB1 receptor antagonist and without. When administered alone WIN reduced hyperalgesia in both cases. The effect of WIN was blocked when the CB1 antagonist was administered to the same location as was the WIN. When the CB1 antagonist was administered to the CNS and WIN to the periphery, it was not able to block the effect of WIN to reduce hyperalgesia. This suggests that systemic administration of WIN produces antineuralgia via both CNS and peripheral mechanisms (7).
The next study may be of little use to most of those suffering from TN, however, it has application to surgeries which pose a risk of TN or other neuropathic pain disorders. In 2007, Guindon, Desroches, Dani and Beaulieu at the Université de Montréal-CHUM reported that the suppression of neuropathic allodynia and hyperalgesia by WIN described previously was significantly enhanced by a one week pretreatment with WIN prior to the neural injury. This suggests that preemptively treating patients with cannabinoids prior to surgery with a high risk of inducing future neuralgia could significantly improve their chances of living a relatively pain-free life in the future (8).
CB1 vs CB2 vs CB1 and CB2
The studies discussed so far have all come to a conclusion that either the CB1 receptor alone (4,6,7) or a combination of both the CB1 and the CB2 receptors (5,8) are responsible for the antineuralgia effects of cannabinoids like WIN. There is however a growing body of evidence to suggest that CB2 receptor activation alone might be enough to produce cannabinoid mediated antineuralgia effects. A new CB2 receptor agonist was found to effectively reduce pain in rat models of neuropathic pain and three other types of pain without significantly effecting motor skills (9). Interestingly, unlike with the CB1 receptor, there is evidence from a mouse model of allodynia that only activation of CB2 receptors in the CNS, but not the periphery, is involved in the anti-allodynia produced by CB2 agonists (10). Yet another study has shown that neither CB1 nor CB2 receptors need be involved in cannabinoid mediated antihyperalgesia, but that cannabinoid mediated activation of vanilloid receptors (TRPV1) was enough (11). This study further suggested that the other terpenes and flavinoids in cannabis may work to potentiate the antinociceptive effect of the primary cannabinoids. Although targeting just CB2 or TRPV1 receptors may be a viable treatment for neuropathic pain, it is beginning to look more and more likely that pan-receptor cannabinoids like THC and WIN will provide the most benefit to the widest number of sufferers of neuropathic pain (12). This leads us to our next question: what role does the endocannabinoid system appear to play in the expression of—or reaction to—neuralgia?
Evidence from the Endocannabinoid System Itself
In 2006, Mitrirattanakul, et al., used the same rat model of neuropathic pain utilized in the majority of studies discussed above to help answer this question. They found that 76 to 83 per cent of the nociceptive neurons near the site of nerve damage expressed CB1 and TRPV1 receptors. After nerve damage, the density of nociceptive neurons expressing CB1 and TRPV1 receptors appeared unchanged whereas both the expression of RNA encoding for the CB1 protein in these cells and the protein itself were elevated, when compared to pre-damage levels. In some of these cells, TRPV1 expression and levels of endocannabinoids anandamide and 2-AG were also elevated (13). Increases in CB1 and CB2 receptor densities have also been observed in both the affected peripheral site and the CNS in a mouse model of neuralgia bearing greater resemblance to TN than the nerve damaged model of neuralgia used in most studies on rats. This study also verified that WIN was able to inhibit neuropathic allodynia and hyperalgesia (14). These findings suggest that the endocannabinoid system is upregulated in effected parts of the nervous system after neuropathic assault. This intern suggests that further manipulating the function of the endocannabinoid system may present a valuable target for future treatments for neuralgia.
Transporter Inhibition vs FAAH Inhibition
There are two primary ways in which manipulation of the endocannabinoid system is currently achieved. One method is to inhibit the enzymes responsible for enzymatic break down of the endocannabinoids such as fatty-acid amide hydrolase (FAAH), the enzyme which deactivates anandamide. FAAH inhibitors or (FAAHI’s) may be the next big thing in cannabinoid pharmacology. We have been utilizing the other method to treat all types of pain for a long time but have only recently come to understand this to be the case. This method is to inhibit the endocannabinoid transporters responsible for removing the endocannabinoids from the intercellular space after they have been released. As it turns out, AM404, one of the main active metabolites of acetaminophen, is an inhibitor of anandamide’s transporter, an agonist at the TRPV1 receptor and a weak agonist at CB1 receptor. [NOTE: Other metabolites of acetaminophen are very toxic to the liver in high doses. DO NOT attempt to take acetaminophen in excess to get high. It will only poison you without producing noticeable psychoactive effects (i.e., you will just get sick and damage your liver).]
So which, if either, of these two methods are useful tools in the fight against neuralgia? So far, it appears that the anandamide transporter inhibitor AM404 is potentially more effective and definitely more reliable at inhibiting the allodynia and hyperalgesia associated with neuralgia. Using rat models of neuropathic pain and inflammation, Mitchell, Greenwood, Jayamanne and Vaughan, 2007, found that one time systemic injections of AM404 reduced evidence of neuralgia associated allodynia but not that produced by neural inflammation. Co-administration of a selective CB1 antagonist completely reversed the affect of AM404 suggesting that CB1 receptor activation was completely responsible for this effect (15). Interestingly, another study published at the same time by Dani, Guindon, Lambert, and Beaulieu, 2007, on local injection of acetaminophen to the site of neuropathic pain (the paw) in a rat model found that acetaminophen inhibited both neuropathic allodynia and hyperalgesia. These antineuralgia effects of local administration of acetaminophen were inhibited by both selective CB1 and CB2 inhibitors. It was unclear from the study if AM404, acetaminophen itself, or one of its other other metabolites were responsible for the apparent CB2 receptor activation (16). This question was answered the year before by Costa and colleagues, 2006. They found a dose- and time-dependant inhibition of allodynia and hyperalgesia following daily administration of AM404 in a rat model of neuralgia. Although this effect was partially inhibited by co-administering a selective CB1 antagonist, a selective CB2 antagonist, or a TRPV1 receptor antagonist, it was only with co-administration of all three together that complete reversal of the effect was observed. This lead Costa, et al., to conclude that the antineuralgia properties of AM404 resulted from activation of multiple endocannabinoid related pathways through the CB1, CB2 and TRPV1 receptors (12). Clearly anandamide transporter inhibition, at least with AM404, is a viable route to helping control neuropathic pain. In light of this, it would be worthwhile to further investigate the use of AM404 to specifically treat TN.
Currently, the picture is a little less straight forward with FAAHIs, especially the most well-studied of them so far, URB597. In 2006, Jayamanne, et al., observed that although systemically administered URB597 was effective in a rat model against inflammation-induced allodynia and hyperalgesia, it was not effective when the two types of pain where neuralgia-induced (17). Interpretation of these results is limited, however, by the fact only one dosage was tested. Later that year, a bit more light was shed on the situation by Jhaveri and colleagues. They found that whether or not local administration URB597 was able to inhibit activation of spinal pain neurons in rats with nerve damage was dependent on if the drug was administered to the site of pain or to the spinal neurons themselves. Only administration to the spine inhibited spinal pain neuron activation in a test of hind leg allodynia. Administration of URB597 to the hind leg also did not increase anandamide levels in the hind leg. In rats without nerve damage, URB597 administered to the hind leg increased anandamide levels in the hind leg while decreasing spinal pain nerve activation. Only when a dose large enough to be potentially systemically active was administered to the hind leg of rats with nerve damage was the activation of the spinal nerves by allodynia in these rats inhibited. In further support that this was not a localized action, anandamide levels in the hind leg were not elevated by the larger dose of URB597 (18). The next year in 2007, Russo, et al., tested how URB597 performed in a mouse model of neuropathic allodynia and hyperalgesia bearing greater resemblance to TN than the rat model in the earlier two studies. Using a wide range of oral doses, they found that systemic URB597 dose-dependently inhibited both allodynia and hyperalgesia induced by chronic nerve constriction. The antinociception produced by this FAAHI was blocked by a cannabinoid receptor antagonist with a moderate affinity for the CB1 receptor suggesting the antineuralgia potential of URB597 is primarily CB1 mediated (19). Recently an endogenous chemical related to anandamide but lacking activity at the CB receptors (palmitoylethanolamide a.k.a., PEA) has been identified as being an endogenous FAAHI. A chemical derivative of PEA know as palmitoylallylamide (PAA) was tested in three rat models of neuropathic pain including the one common to many of the other studies covered in this article. It was found to be effective at reducing expression of allodynia and/or hyperalgesia in all three models without effecting motor skills. In the most commonly used rat model of neuralgia discussed so far, antineuralgia effect of PAA was found to be partially inhibited by either CB1 or CB2 antagonism (20).
It appears that anandamide transporter inhibitors like AM404 may prove to be particularly useful in the management of TN. In high enough doses or when applied more directly to the damaged nerve, URB597 may also prove useful. On the plus side, URB597 appears to have a very wide therapeutic margin when administrated orally so larger doses would not likely be an issue. New endogenously derived FAAHI’s may prove more effect against TN and especially well tolerated. One question that has yet to be addressed is how well the two types of endocannabinoid manipulation might perform when administered together as a single combined treatment. This combination may just prove to be the most effective yet.
Although there do not yet appear to be any human studies of cannabinoids used in the treatment of TN, there are however many anecdotal reports available concerning TN patient experience with preparations of cannabis to alleviate a degree of their pain.
Sherrie Toland, 40, having especially rare bilateral TN since childhood, has been diagnosed suicidal over it in the past:
[blockquote style=”style-1″] “And I’ve tried everything. Now I’m told none of the surgeries or even the latest and greatest Gamma Knife is likely to work. And since I’ve had this since childhood, I can understand why it wouldn’t. Too little, too late. But I can’t understand why I can get prescriptions for opiates on top of opiates and then more and more sedatives and anti-depressants. It’s enough to drive one crazy.[/blockquote]
And the bottom line: marijuana works better than opiates and using it I would not need as many opiates. At the worst in my case, wouldn’t marijuana be the lesser of two evils? I truly worry about all the opiates, and I don’t want to be an addict (21).”
Multiple Sclerosis patients develop TN at a higher rate that the rest of the population due to MS related demyelination of the trigeminal nerve. MS is also one of the more widely accepted uses of cannabis therapy. Therefore more TN patients with MS than without report on the efficacy of cannabis preparations to treat TN. “Wolfalohalani” of Portland, OR, is one such MS/TN patient. He says:
[blockquote style=”style-1″]“If I can catch an attack when it’s first starting out, I can hold some glycerine tincture at the hinge of my jaw on the effected side and it will numb the area and back the pain off. If I really don’t want to feel any alteration of consciousness, I can wait five or ten minutes, and then spit the remaining extract out. What has already absorbed will last half an hour or so – enough time for the attack to be over (22).”[/blockquote]
Interestingly, Wolfalohalani’s statement that if “I really don’t want to feel any alteration of consciousness, I can wait five or ten minutes, and then spit the remaining extract out” fits very well with the observation by Fox, et al., 2001, that non-systemically active doses applied locally in the periphery were able to alleviate neuralgia-induced hyperalgesia. This suggest that transdermal patches of cannabinoids or endocannabinoid modulators applied to the effected side of the face may prove useful at alleviating TN associated pain for some. Lozenges may also be a highly viable option.
Alison Myrden, a member of TreatingYourself.com, has MS and TN as well. She’s about 40 and is a member of the Canadian branch of LEAP (Law Enforcement Against Prohibition). She describes the state of pain produced by TN as being epitomized by The Scream, painted by Edvard Munch, saying that the pain is like a “bolt of lightning shooting through my face.” When it occurs, the pain is almost nonstop, completely intense suffering. When she was taking large quantities of opiates to deal with this pain, she would get them for $2 a pop but could sell them on the street if she so chose for $20-$30 per pill. (She never gave into this temptation but nonetheless it was always there). As a result, she says, “I had people offer me to sell my medication to make me rich.” Furthermore, it took heroic doses of opiates to even touch her pain. Many TN patients find themselves here. For her, smoking high quality therapeutic cannabis is the only thing that will help reliably alleviate the pain of an episode of TN to any significant degree. She says, “nothing else will help, this is the only thing that gives me relief (23).”
Few may know the true horrors of living with TN, but for those who do, escaping that hell at any cost, even death, becomes a strong motivator. The scientific/medical and legal communities should be equally motivating to find and authorize any non-fatal means of helping these patients achieve this end. The currently approved treatments that show the most efficacy and promise so far are also the most risky and involve irreversibly cutting or killing the nerves responsible. Furthermore, current pharmacological options appear to be effective in the long term for only about half those effected. Many will have a positive initial reaction only later to develop tolerance or insensitivity to the drugs.
In both animal tests and anecdotally in humans cannabinoids have proven effective treatments in the management of TN. Modulators of the endocannabinoid system have also shown much promise. The mechanism of action appears to be both mediated by the peripheral and the central nervous system, indicating that, for some cases, peripheral administration may be enough. It is time their efficacy was properly studied in humans. For those unable to last that long, glycerine-based tincture appears to be a good starting place. For those for whom peripheral administration is not enough, vaporized cannabis may be required to get the full combined peripherally and centrally mediated antinociceptive effect. Either way, it is time we address the needs of the other 50 per cent not able to get long term relief from their trigeminal neuralgia from currently approved medications. Allowing the condition to beat them down into the final submission should not be an option.
I would like to offer special thanks to my sister-in-law, Jenny, her sister Meg, and Meg’s husband Sam who suffers from TN for bringing this condition to my attention and inspiring me to write about it. I would also like to thank all those who have reported on their own experience here.