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8 Articles in Volume 6, Issue #6
Choosing and Using a Low Level Laser in Pain Management
Clinical Bioethics
Cranial Electrotherapy Stimulation in the Treatment of Fibromyalgia
Fibromyalgia: New Hope and New Pharmaceuticals
Identifica tion and Management of Cardiac -Adrenal-Pain Syndrome
Interventional Therapy
Superior Pharyngeal Constrictor Muscle Pain
Treating Neuropathic Pain in Multiple Sclerosis (MS)

Treating Neuropathic Pain in Multiple Sclerosis (MS)

MS patients with neuropathic pain demonstrated improvement using the oral synthetic cannabinoid nabilone.

Multiple sclerosis is a chronic demyelinating disease of the central nervous system (CNS). The severity and type of associated neurologic symptoms is dependent on the location and degree of myelin loss and axonal degeneration.1,2 Symptoms are characteristically progressive, relapsing and remitting, and may be associated with disability and impairment. Typical symptoms include: tremor, ataxia, muscle spasm, weakness, paralysis, difficulty speaking, constipation, loss of bladder control, and pain.3

Approximately 70% of MS patients suffer from pain and 8% of patients report that pain was the first noticeable symptom of the disease.3 Pain symptoms were more frequent among patients with higher EDSS scores or spinal cord involvement.3 Although pain in the MS population may not be more frequently reported than in the general population, pain intensity, the need for analgesia and the impact of pain on activities of daily living is reported to be higher in patients with MS.4-7 Paradoxically the most severe patients are often resistant to the standard therapy (i.e. topical analgesics, tricyclic antidepressants, gabapentenoids, opioids, etc.)

In this article, we will present case studies of multiple sclerosis patients with neuropathic pain improved with the oral cannabinoid nabilone. This synthetic nitrogen-substitution analogue of delta-9-tetrahydrocannabinol (THC), indicated for anorexia and nausea in cancer chemotherapy patients (Canada and United Kingdom), is also used off-label for pain management. It is more water soluble than THC. Compared to oral THC, it has a more rapid onset of action, longer duration of action, and shorter half-life.8,9

Recent theoretical and technological advances in neurobiology, neuroimaging, neurophysiology, the mapping of cannabinoid receptor sites, the discovery of both exogenous and endogenous ligands, and the investigations of the link between heavy metal toxicity and MS all seem to be converging.2,4,10-14 Despite these space age advances, some patients are as stubbornly resistant to treatment now as they were in the nineteenth century, when the disease was first scientifically described in the literature.

Table 1. Patient Characteristics Prior to Prolotherapy
Patient; MS class Date of Birth; Gender Dose of Nabilone Date of initial treatment; Duration up to date of data collection Neuropathy Pain Scale (0=none to 100=worst) Extra Notes
        Before After  
A
RR
07/26/39
Female
1mg/
night
June 8/05
14 months
43 31
  • nabilone helped dull the pain
  • overall sleeping is better now
  • Patient ceased anxiolytic medication
  • patient tapered opioid medication
B
AM
03/13/43
Male
1mg/night Mar 21/05 17 months    
  • Some relief at night
  • Able to control pain much better when nabilone is taken with oxycontin (opioid synergy)
C
SP
06/9/49
Male
0.5mg/
night
Dec 1/05
9 months
35 22
  • Helps in falling asleep
  • Increases overall comfort and reduces pain
  • Reduced muscle spasticity, anxiolytics, opioids
  • Increased range of movement and strength
D
AM
11/8/65
Male
1mg/
night
Mar 1/06
5 months
52 33
  • Reduction in overall pain
E
AM
02/07/67
Female
1mg/
night
Feb 3/06
6 months
60 40
  • Able to sleep better with no interruptions
  • After nabilone she was able to reduce the amounts of other medications
  • Decrease in anxiety and nausea
  • Less depressed
  • Increased range of movement-able to get out of her wheelchair and play with her daughter
F
SP
06/23/58
Female
1mg/
night
June 21/06 2 months    
  • Opioid sparing
    To early to tell, has not come back for check up yet
G
RR
06/16/44
Male
1mg/
night
July 4/05 13 months    
  • Promising. Temporarily stopped.
H
PP
11/2/34
Female
0.2mg/ night October 26/05
9 months
56 45
  • Able to sleep for first time in 10 years, highly sensitive to adverse drug reaction (ADR)
  • Dispensed as aqueous solution 0.2mg/ml titrated up to 30 drops qhs sublingual
  • Only prescription medication she is on now
I 06/28/62
Female
1mg/
night
Jan 24/05
4 months
63 39
  • Headaches and migraines completely gone
  • Says she feels like a completely different person
 

Could it be that the proper understanding of cannabinoid chemistry, neurobiology, and pharmacokinesis holds the key to unlocking the complex chimaera of the etiology, diagnosis and treatment of the different manifestations of MS?1,9,15-18 In fact, recent publications have indicated that cannabinoids may have significant efficacy in the treatment of chronic neuropathic pain in the MS population.18,19

Case Studies

The case studies analyzed in this article included varying classifications of MS: (1) primary progessive, (2) relapsing remitting, (3) secondary progressive, and (4) atypical MS. The diversity of this patient population and associated medication needs mandated different modes of ingestion, dosages, and titrations of nabilone. The positive results encountered across such a varied MS patient cross-section points out a need for formal double-blind randomized placebo-controlled trials having proper neurophysiological measures and drug pharmaco-kinetic labwork. Nevertheless, the cases studied demonstrated meaningful results and are presented in summary form (see Table 1) along with a few selected detailed case studies that were indicative of typical results.

An overall summary of the study objective, setting, subjects, outcome measures, interventions, and general results are summarized below:

  • Objective: To report on a case series of MS patients effectively treated for neuropathic pain using oral cannabinoid (nabilone).
  • Settings: University Teaching hospital outpatient clinics.
  • Subjects: MS patients with neuropathic pain referred from family physicians and neurologists. Patients were pre-screened with the DN4 questionnaire for neuropathic pain and the EDSS. They were also excluded if there was any significant addiction risk or psychiatric comorbidity.
  • Outcome measures: Numerical rating scale for pain, Short-form McGill Pain Questionnaire, Pain Disability Index, Neuropathic Pain Scale, Pain Diagram. Physical examination also included jamar grip dynamometry and neurological assessment.
  • Interventions: These patients were initiated with low dose nabilone starting with 0.5 mg at night. Some patients were titrated up to higher doses. Two patients were highly medication sensitive and responded better to a sublingual aqueous mixture of nabilone at 0.2 mg/ ml. Concomitant medications and therapies were monitored. Duration of treatment varied from one to 18 months.
  • Results: These patients improved significantly in most outcome measures. In several cases, the use of opioids and psychotropic medications were reduced or eliminated. No major adverse reaction, habituation, or tolerance developed. Quality of life and sleep were also improved subjectively in patient diaries.

Case Detail #1 (Patient C)

A 57 year old former can factory manager, married father of two, has chronic secondary progressive MS. In 2002, his condition was further complicated after undergoing surgery for cervical stenosis. Past medical history includes thyroid disease, carpal tunnel release, vasectomy, and tonsillectomy.

His medications included Baclofen, Effexor, Alertec, Gabapentin 400mg qid, and Oxycocet 3 per day, on average, for breakthrough pain, as well as Duragesic patch titrated at 100mg every two days. He had received regular Botox injections for spasticity primarily in his legs.

Physical exam revealed a height 5’ 7" with weight 150 lbs. Blood pressure (BP) was 133/98 mmHg. Neurological examination revealed signs of spasticity involving all four limbs. He had both knee and ankle clonus bilaterally and walked with a broad-based gait with the ankles plantar flexed. Spasticity was a dominant feature in the upper extremities with slow movements of the arms and limbs. He was able to abduct his shoulders to 90 degrees. He described tightness in the shoulders on doing so. He also described a numb-like sensation that radiated from the shoulders down towards the elbows. Prior to taking nabilone, his neuropathy pain scale rating was 35.

He was started on nabilone at 0.5 mg QHS and noted reduced muscle spasticity in his arms, and reduced intake of anxiolytics and opiods. He also noted an increased range of movement (shoulder abduction to 120 degrees) and prehensile strength. He reported being able to fall asleep better at night, an overall decrease in pain, and an increase in comfort. After taking nabilone for three months, his neuropathic pain scale was down to 22.

Case Detail #2 (Patient E)

A 39 year old former promotions worker, remarried mother of one, was diagnosed by one neurologist as having atypical MS and by a rheumatologist as having severe fibromyalgia (FMS) and chronic pain syndrome. She reported developing much of her severe pain starting in the early 1990’s. Prior to the diagnosis of FMS/MS in 1991, she had a slip and fall accident where she landed squarely on her right hip and had ongoing pain complaints. Previous treatments included acupuncture, physiotherapy, and massage which she still found helpful. In 2002, she came down with appendicitis. Her hospital stay was complicated by seizure-like activity.

Her medications before nabilone included Effexor XR, Codeine, Alprazolam, Nova- Hydrazide, Nasonex spray, and Sodium Sulamyd eyedrops. She had also tried long-acting morphine. She regularly used a hot tub at home which helped with muscle pains and spasms.

When first seen, she described the pain as being everywhere. She described pins and needles in both feet. She also described numbness in the arms, going into the hands, in the legs and down into the feet. Other symptoms noted included nausea, vomiting, decreased appetite, and decrease in vision, impaired speech, restless legs/cramps, intermittent seizures, loss of bladder/bowel control, skin rash, swelling, joint “clicking," and morning stiffness for about an hour. She had difficulty falling asleep and usually woke up tired in the morning. Her level of disability was such that she could not walk, drive, cook, vacuum, play with her daughter, nor engage in any hobbies. Her neuropathic pain scale before nabilone was 60.

“…recent publications have indicated that cannabinoids may have significant efficacy in the treatment of chronic neuropathic pain in the MS population."18,19

Her physical exam revealed a height of 5’ ¾" with a weight of 130 lbs. BP was 106/75 mmHg. She had widespread allodynia to light touch and was tender over all 18 FMS points. She was in a wheelchair and had difficulty moving her legs to transfer or stand up. Reflexes were brisk diffusely but without any sustained ankle clonus. Babinski’s were equivocal. Hoffman’s responses were positive bilaterally. Jaw jerk could not be done due to pain inhibition.

She was started on nabilone 1mg QHS. She reported being able to sleep much better with no interruptions during the night. She also described feeling less depressed and a noticeable decrease in nausea and anxiety. The amount of medications she took had also been reduced, most notably Effexor, Alprazolam, and opioids. She reported an increased range of movement, and could now get out of her wheelchair and play for a short while with her daughter. After taking nabilone for 6 months, her neuropathic pain scale was 40. (She continues taking this 18 months later).

Case Detail #3 (Patient H)

This 71 yr old woman was seen with primary progressive MS. She had not worked since 1987 at the time of her diagnosis. The course of MS had been aggressive leaving her wheelchair bound for 2 years. Before that she used a walker for 15 years. She lives with her semi-retired accountant husband. She required attendant care daily and used a motorized wheelchair for all her office visits. On one of her assessments (a house call visit), she presented with a good attitude. Her home appeared neat and tidy. Despite this, she still had severe burning pain throughout her spine and legs. She had not been able to have a good night’s sleep for the past ten years. She was very intolerant to most drugs such as tricyclics, anticonvulsants, non-steroidal anti-inflammatories, and low dose opioids due to excessive nausea, gastrointestinal distress, dizziness.

Prior to nabilone, her neuropathic pain scale was 56. She attempted nabilone initially at 0.5 mg at night but reported being overly sedated at that dosage. After taking nabilone at a lower dose in suspension, she described many of her symptoms as being greatly decreased. She says she is now able to sleep well for the first time in ten years. After taking nabilone, her neuropathic pain scale dropped to 45. She noted that it was the only prescription medication that had reduced her pain and improved her lifestyle without side effects, allowed her to sleep, and improved, somewhat, her level of function (ability to transfer, dress, feed). Recently, she was contacted by phone and reported that with nabilone drops, she felt the best she had in 20 years.

Discussion

Current protocols for the management of multiple sclerosis stress the need for therapies directed at symptom management and disease modulation. Yet the most severe pain patients are often refractory to the standard therapy, but quite receptive to low dose sublingual cannabinoid therapy. It seems that cannabinoids may play multiple roles in the treatment of MS.

In the neurobiology model, the effectiveness of the cannabinoid mechanism of action (endogenous system with receptors and ligands to exogenous stimulation) is linked to the particular ligand in question (CB1, CB2, or CBD) and the binding site, which may be local or central or at the dorsal horn of the spinal cord. The receptor sites which are considered to be active are CB1, CB2, or CBD, and the mu opiod receptor site. The pharmacokinitecs of nabilone is determined by the unique biochemistry of an individual. Dosage must therefore be monitored and titrated on an individual basis.20

Cannabinoid’s apparent synergy with opioids, in terms of pain management, is modelled as a utilization of both different and similar receptor sites. Nabilone has an opioid sparing effect as seen in our patient population.21 The net effect is that dosages of other medication (e.g., opioids and anxiolytics)22 can often be carefully titrated down as nabilone is added to their regime.

Ancillary Effects

Improved sleep is apparent in our study population. Sleep studies done with our patients—once titrated down on other medications and stabilized on nabilone—reveal less interruption, more REM sleep, and more stage IV EEG sleep. In essence, a more normal sleep architecture. This has been substantiated in formal sleep studies done with some of the patients in our cohort. Reduced anxiety has also been noted in our patient population and in the literature. This is also a direction for further controlled studies. There is both a stand alone effect and a synergy with anxiolytics such as benzodiazepines.22

Another ancillary effect of nabilone is the control of spasticity. There is also some evidence that nabilone improves nocturia.8

Disease Modification

Cannabinoids have been shown to have immunomodulatory effects including: anti-inflammatory properties, down regulation of T helper 1-cytokines, and enhancement of the production of TH-2 (protective) cytokines. This shift has also been shown to be of therapeutic benefit in MS. Also, CB’s exert a neuromodulatory effect on neurotransmitters involved in the neurodegenerative phase of MS and reduce expression of major histocompatibility complexes – type II (MHC–II).23

It is the case that in MS patients, especially the more severe and/or long standing patients, that they are refractory or experience adverse drug reactions with the standard therapy for their condition. It is in this particularly difficult population that nabilone shines most brightly as a promise for future research.

There may be no other drugs for it to be synergistic with and its stand alone action, which is seen with some of our study patients, is in administering very small aqueous solution doses of nabilone, sublingually, by the drop, under the tongue. It is hypothesized that its documented effectiveness with this patient population is by gently stimulating the brain’s own manufacture of endocannabinoids. Our observations appear to substantiate the endocannabinoid model of the etiology of MS, and suggest a new paradigm and model for further research

Endocannabinoids

The endocannabinoid model of MS etiology has been described in the literature. This novel mode of ingestion stimulates endocannabinoid production in a manner similar to homeopathic sublingual formulations in accordance with the Arndt-Scultz rule, where a smaller dose is more potent than a larger dose. The production centrally of endocannabinoids is triggered in a manner akin to the production of endorphins, centrally, by acupuncture.

A further point of intersection between the neurobiology of endocannabinoids and mode of ingestion is a transdermal delivery system for a correct dosage of cannabinoids to the actual site needed with minimal adriamycin ADR and central nervous system toxicity. This will be the subject of our future clinical research.

Conclusion

This study suggests that nabilone appears helpful in MS patients with neuropathic pain. Improvement in such symptoms such as muscle spasticity were also noted. Improvement in symptoms such as fractured sleep architecture, anxiety, depression, and functional abilities were also noted. The evidence garnered supports the endocannabinoid model of the etiology of MS. More severe patients seemed to be helped more by lower doses and alternative modes of absorption e.g. sublingual and transdermal (under investigation). Further randomized controlled trials will be needed, to validate each of these preliminary findings.

Disclosure

Financial assistance from Valeant Pharmaceuticals is acknowledged in the writing of this article.

Last updated on: November 6, 2012
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