Spasticity is a central feature of multiple sclerosis (MS) and spinal cord injury (SCI). It consists of a velocity-dependent increase in tonic stretch reflexes with exaggerated tendon jerks, resulting from hyperexcitability of the stretch reflex as one component of the upper motor syndrome (Young 1994). Existing drug therapy is far from satisfactory in terms of efficacy and unwanted effects (Panegyres 1992). Tremor, ataxia and lower urinary tract symptoms are frequently troublesome in MS. Both neuropathic and nociceptive pain (dealt with in Sect. 2.3) are also common in MS and SCI, and dozens of very painful muscle spasms can occur each day. Small wonder that there is also a high incidence of anxiety and depression in these conditions.
THC and other cannabinoids have been shown (Baker et al. 2000) to improve both tremor and spasticity in a well-validated animal model of MS (experimental allergic encephalomyelitis). Antagonism of the CB1 receptor aggravated these signs, indicating a role for endogenous cannabinoids in the control of tremor and spasticity.
Many patients have reported anecdotally that cannabis can relieve some of the most distressing symptoms of MS and SCI, including spasticity, muscle pain, tremor, spasms on walking, paraesthesiae, leg weakness, trunk numbness, facial pain, impaired balance, nystagmus, anxiety and depression (Grinspoon and Bakalar 1993; Consroe et al. 1997). Hodges (1992) described the severe progression of her MS from its onset in 1983. Prescribed medicine was only moderately effective and produced unpleasant side-effects. Having with reluctance and no small difficulty established an illicit supply of cannabis, she wrote:
When I smoke it, my body completely relaxes, which relieves the tension and spasms I have. It has had other beneficial effects. I am now more efficient at controlling my bladder, so I don't get the recurrent urinary infections that I was having before. It relieves my nausea and I can now sleep much better, so that I am not tired all the time.
Malec (1982) reported that 21 out of 24 SCI patients with spasticity who had tried cannabis found it had alleviated their symptoms. A recent survey of MS patients in the UK and USA found that between 30% and 97% experienced relief in symptoms with cannabis, depending on the particular symptoms (Consroe et al. 1997). In descending order of improvement, these were: spasticity, chronic pain, acute paroxysmal phenomena, tremor, emotional problems, anorexia/weight loss, fatigue states, double vision, sexual dysfunction, bowel and bladder symptoms, vision dimness, difficulty with walking and balance, and memory loss.
Open or single-blind observations of small numbers of patients on the effects of synthetic THC given orally have provided some support to these reports (Dunn and Davis 1974; Petro 1980; Clifford 1983; Meinck et al. 1989; Brenneissen et al. 1996). Subjective improvements in spasticity are a consistent finding, with some studies also indicating benefits for tremor, bladder control, mobility and mood. Unwanted effects do not seem to have been prominent. Schon et al. (1999) reported amplitude reduction of pendular nystagmus and improved visual acuity in an MS patient following smoked cannabis, but no effect following cannabis capsules or nabilone (a synthetic THC analogue). Of related interest is a report from Russo et al. (2003) describing improved night vision following both THC and cannabis in a single subject.
Brady et al. (2003) carried out an open pilot study in 15 MS patients with refractory lower urinary tract symptoms. They each received whole plant cannabis medicinal extracts (CBME) containing either predominantly THC or an equal proportion of THC and CBD for consecutive 8-week periods. Incontinence episodes, nocturia episodes, incidence of urinary urgency and frequency all decreased significantly, whilst the number of planned or normal voids significantly increased. Most patients experienced mild intoxication during the initial titration phases and two had short-lived hallucinations that disappeared on dose reduction. The authors concluded that CBME may prove to be a safe and effective additional treatment for this harrowing condition. A pilot open label study in 15 patients with overactive bladders as a result of SCI also showed symptomatic improvement following 10 mg THC by either oral or rectal routes (Hagenbach et al. 2001).
The first double-blind placebo-controlled study in MS patients was reported by Petro and Ellenberger (1981). Oral THC in a single dose of 5 or 10 mg was compared with placebo in a crossover design in 9 subjects. Both doses of THC were significantly superior to placebo in relieving spasticity measured by clinical examination or, where feasible, electromyography during quadriceps stretching. One patient receiving THC 10 mg and one receiving placebo reported feeling "high". Ungerleider and colleagues (1987) found in a randomised double-blind crossover study with 5-day treatment periods that THC 7.5 mg produced significantly improved patient ratings of spasticity in comparison with placebo. In a double-blind, placebo-controlled crossover trial Hanigan et al. (1985) reported that THC 30 mg/day for 20 days significantly improved objective measures of spasticity in 2 out of 5 patients with traumatic paraplegia. Martyn (1995) reported that nabilone 1 mg on alternate days for 1 month was better than placebo in a double-blind crossover study in a single MS patient. Improvement in nocturia, muscle spasm and general well-being were also noted in this patient, with mild sedation the only unwanted effect. On the negative side, a single dose of smoked cannabis (THC content 1.54%) impaired both posture and balance in comparison with placebo in 10 MS patients and 10 normal subjects (Greenberg et al. 1994), a not-unexpected occurrence with any skeletal muscle relaxant.
More recent trials of cannabis-based medicines in MS have given mixed results. Vaney and colleagues (2002) enrolled 57 MS patients in a randomised, crossover comparison of 15 mg THC daily in divided doses for 15 days with placebo. A significant improvement in a subjective rating of spasm frequency was not accompanied by objective improvement as represented by the Ashworth Score (Ashworth 1964). This is a measure of biological impairment, as opposed to disability or handicap, and relies upon an estimation by a clinician. A trend towards improvement in mobility was noted, but no effect on tremor, sleep quality, or lower urinary tract symptoms. Adverse events occurred with similar frequency in the active and control groups, but were more severe in the former. Killestein et al. (2002) reported an unambiguously negative study in 16 MS patients. In a randomised, double-blind crossover design, they compared synthetic THC with a cannabis plant extract containing the same amount of THC and placebo over 4 weeks of treatment. Starting dose was 2.5 mg orally twice daily, with the option to increase this to 5 mg twice daily after 2 weeks if the first dose was well tolerated. There was no improvement in spasticity as represented by the Ashworth Score. Both active medicines were well tolerated, but were inferior to placebo in terms of the patients' subjective global impression of change. An accompanying editorial (Thompson and Baker 2002) pointed out that the study was not powered to detect efficacy, and the writers drew attention to the difficulty in achieving the most appropriate individual dose by the oral route.
Theverylowwatersolubilityofkey cannabisconstituentsaggravatesstillfurther the well-known variability of absorption from the gastro-intestinal tract, resulting in poor predictability of both the timing and intensity of peak effects by the oral route. Titration of dose against symptom relief, as is the norm for most individuals who smoke cannabis medicinally, is very difficult in these circumstances. An additional drawback is the production of larger quantities of the reputedly psy-choactive metabolite 11-OH-THC as a result of the hepatic first-pass phenomenon. The use of whole plant cannabis-based medicinal extracts in liquid form delivered by a pump action oromucosal spray (Whittle et al. 2001) represents an attempt to overcome these problems and permit the patient to self-titrate to an optimal individualised daily dose.
This mode of delivery was utilised in a consecutive series of double-blind, randomised, placebo-controlled single patient crossover trials with 2-week treatment periods (Wade et al. 2003). Twenty-four patients received whole plant extracts by oromucosal spray containing primarily THC, primarily CBD, an equal propor tion of THC and CBD, or matched placebo at doses determined by titration against symptom relief or unwanted effects within the range 2.5-120 mg/24h(1-48 sprays). Eligible patients had neurogenic symptoms which had responded poorly to standard treatments, and the majority had MS or SCI. Patients recorded symptom, well-being and intoxication scores on a daily basis using visual analogue scales (VAS), completed standard measures of disability, mood and cognition on regular clinic visits, and recorded adverse events. Average dose following self-titration in the active treatment groups was around 9 sprays/24 h. At the nursing assessments, all three CBMEs significantly improved the subjective measure of spasticity in comparison with placebo, and both THC CBME and THC: CBD CBME improved muscle spasm. Patients' daily diaries showed that THC CBME significantly improved VAS scores of pain, muscle spasm and spasticity, THC: CBD CBME significantly improved spasm and sleep, and CBD CBME significantly improved pain. Four patients withdrew due to unwanted effects, and the percentage of patients with at least one adverse event was considerably higher when THC was not accompanied by an equal proportion of CBD (55% vs 30%). The authors concluded that CBME can improve neurogenic symptoms unresponsive to standard treatments, and that unwanted effects were predictable and generally well tolerated.
An important trial funded by the UK Medical Research Council ("CAMS" study) has explored the effects of synthetic THC (Marinol) and a cannabis extract ("Can-nador") given orally on spasticity and other symptoms related to multiple sclerosis (Zajicek et al. 2003). This was a randomised, placebo-controlled trial involving 33 centres and 630 patients, and the primary outcome measure was change in overall spasticity score as represented by the Ashworth scale.
The results of the study were mixed, and a large placebo effect was noted. There was no change in Ashworth score following 15 weeks of treatment with either THC or Cannador, but both active treatments demonstrated significant improvements in subjective measures of spasticity, muscle spasms, pain and sleep, and also in an objective measure of mobility. No effect was apparent on irritability, depression, tiredness, tremor or loss of energy. The authors noted an unexpected reduction in hospital admissions for relapse in the two active treatment groups. The known interaction of cannabinoids with the immune system, and the fact that MS is still regarded as an auto-immune condition led them to comment that this finding was worthy of further investigation. Minor unwanted effects were frequently reported in all three treatment groups, with a higher prevalence for the active treatments. The small number of serious adverse events were evenly spread across the three groups.
The limitations of the Ashworth scale in measuring such a complex phenomenon as spasticity is well known (Hinderer and Gupta 1996) and is acknowledged by the authors. They also noted that the evidence in support of currently available standard drug treatments for spasticity (and many other MS-related symptoms) is weak. Although the study incorporated a titration phase, the fixed twice daily dosing routine was not ideal in seeking to allow patients to optimise the balance between positive and negative effects given the known variations in individual response. An accompanying Lancet editorial (Metz and Page 2003) drew attention to the high variability in degree of spasticity among the trial patients and com mented that the primary outcome measure does not correlate with function or other measures of spasticity. It recommended that "future studies should consider the potential confounding effect of including ... patients with severe spinal cord disease and should not rely totally on the Ashworth scale". It was also noted that poor bioavailability of oral cannabinoids may have influenced the outcome.
A significant effect upon a subjective measure of spasticity was the principal finding in another large study of cannabis-based medicine in MS (Wade et al. 2004). The effects of a whole plant extract containing an equal proportion of THC and CBD (Sativex) was compared with placebo in a parallel-group, double-blind, randomised study in 160 MS patients. Eligible patients were experiencing one of the following symptoms which had proved refractory to standard treatment: spasticity, muscle spasms, lower urinary tract symptoms, neuropathic pain or tremor. An oromucosal spray delivered 2.5 mg of each cannabinoid or matched placebo on each activation. After initial standardised dosing in an outpatient clinic, patients gradually titrated the dose upwards at home to a maximum of 48 sprays/24 h, aiming for an optimal balance between symptom relief and unwanted effects. Treatment period was 6 weeks, and the primary outcome measure was a composite derived from the VAS score of each patient's most troublesome symptom. Secondary measures were individual symptom VAS scores, and standardised measures of disability, cognition, mood, sleep and fatigue.
Once again, there was a strikingly large placebo effect. The composite score (max 100) following Sativex fell from a mean (SE) of 74.4 (11.1) to 48.9 (22.0) and from 74.3 (12.5) to 54.8 (26.3) following placebo (ns). Spasticity VAS scores fell by 31.2 following Sativex and by 8.4 following placebo [difference =-22.8; 95% confidence interval (CI): -35.52 to -10.07, p = 0.001]. Statistically non-significant improvements were also seen for spasms, bladder control and tremor. A similar pattern of responses was also noted from diary symptom VAS scores recorded by patients on a daily basis. Patients using Sativex assessed the quality of their sleep as significantly improved (p = 0.047). No significant adverse effects on cognition or mood were noted. Sativex was generally well tolerated. In particular, intoxication was usually mild, and largely avoidable with careful dose titration.
Clearly, further work is required to clarify the exact role of cannabis-based medicine in the symptomatic treatment of MS and SCI. Perhaps the position at the time of writing is best summarised by the comments of the Chief Executive of the Multiple Sclerosis Trust on the results of the CAMS study. In a press release on 7 November 2003, he stated:
It is frustrating that the results of the study are somewhat equivocal. We are pleased that the CAMS study confirms the strong anecdotal evidence of the benefit of cannabis for some people with MS. It is particularly encouraging that patients receiving cannabis perceived an improvement in both spasticity and pain, when compared with those on placebo, and that no significant side-effects were reported. However, it is clear that the primary assessment tool used to measure spasticity, the Ashworth Scale, has failed to capture the full impact of this aspect of MS. Spasticity is a complex collection of symptoms encompassing pain and stiffness, some of which can only accurately be as sessed using subjective measures. However, overall, we believe that this study, combined with others which demonstrate symptomatic improvement, provides convincing evidence that cannabis may be clinically useful in treating some of the symptoms of MS.
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