Antonio, aged 73, has been affected by primary progressive multiple sclerosis for the last 15 years. He has an ataxic gait, he sometimes stumbles and teeters, his hands have progressively lost strength and a slight tremor has appeared. His way of speaking has become hesitant and lately he has manifested a certain emotional lability, to a point that he has started taking an antidepressant (citalopram) upon the suggestion of his neurologist. He has followed for years and with constancy a rehabilitative physiotherapy treatment and takes myorelaxants (baclofen and clonazepam) to improve spastic rigidity. As additional therapy, he takes a calcium antagonist (nitrendipine) for a slightly high blood pressure and a long-acting bronchodilator for COPD.
In the last few months, the worsening of rigidity and hypertonia and the appearance of painful spasms, especially in the nocturnal hours, have brought the neurologist to prescribe Antonio a new therapy based on derivatives of Cannabis sativa. After an initial dose titration phase, the treatment consisted of eight daily applications (16.2 mg of tetrahydrocannabinol per day). Two months after the start of the therapy, the patient has visibly gained weight (9 kg), appears weary, dyspnoic, his ankles and feet are clearly oedematous to a point that he cannot wear shoes. His wife reports that the painful cramps during the night have improved but not the insomnia, whilst during the day her husband is sleepy, little reactive, often falls accidentally and also complains of nausea, severe constipation and significant halitosis. The lab tests reveal normal values. Few weeks later the inversion in the sleep-wake rhythm still persists like the falling, whilst the weight remains constant. At the following visit, the neurologist decide to discontinue the therapy with cannabinoid.
There is an explanation for everything
Nabixilol is an oromucosal formulation containing tetrahydrocannabinol (THC) and cannabidiol (CBD) in 1:1 ratio and it is registered in Italy for the treatment of symptoms correlated to spasticity in patients affected by multiple sclerosis. The effects of THC and CBD can be ascribed to their interaction with the receptors for endocannabinoids diffusively present in the organism and involved in the regulation of several physiological processes. Up to date two receptor populations have been identified: CB1 receptors, largely expressed within the central nervous system but recently identified also at a peripheral level (for example in the blood vessels and in the gastrointestinal tract) and CB2 receptors, principally localized a the immune system level.
The patient in exam has some peculiar characteristic as, after two months of therapy only, he has reported several adverse events that, even though not severe, have nevertheless limited his quality of life.
The weight gain has to be ascribed to the effect of THC on CB1 hypothalamus receptors. Cannabinoids, in fact, exert an anabolic action which facilitates the food intake by stimulating, when the “signal” is in excess, fat accumulation. Some evidences indicate that this action is mediated by the reduction of leptin levels. This hormone represents, in fact, the first signal the hypothalamus uses to regulate the sense of fullness and the energetic metabolism, by producing neuropeptides that reduce hunger sensation. Therefore, the reduction of leptin levels caused by THC determines a general orexigenic action, a well-known phenomenon among Cannabis consumers.1
The frequent falling can be linked to the presence for this patients of more risk factors, such as the multiple sclerosis-induced ataxia, the frequent sedation/vertigo induced by the cannabis and, also, the reduction of spasticity in a subject whose muscular strength is not anymore sufficient to guarantee an adequate posture.2
The ankle oedema and constipation are not-reported adverse events in the medication data sheet but, presumably, they have been caused by the synergic action of the calcium antagonist taken by the patient with the nabixilol. Some evidences indicate that the endogenous cannabinoid anandamide, bounding to the CB1 receptor, induces vascular smooth muscle relaxation by inhibiting the calcium voltage-dependent channels.3 The consequent vascular dilatation determines an increase in the hydrostatic pressure in the microcirculation of the lower limbs, with the appearance of the oedema. This effect could have also been accentuated by the THC inhibiting effect on CYP3A4 cytochrome, the enzyme responsible of nitrendipine metabolism, with consequent possible increase of calcium antagonist blood concentration.
A plausible hypothesis for the inversion of the sleep-awake rhythm manifested by the patient could find an explanation in the opposite effects of THC and CBD on the CB1 receptor. In particular, one the effects ascribed to CBD is the increase in vigilance that contrast the already cited sedative effect induced by THC.4 It has still to be evaluated whether the concomitant administration of an antidepressant could have been constituted a concomitant cause for the sleep disorder reported by the patient.
Up to date, the Italian National Pharmacovigilance Network has registered 148 suspect adverse reactions to nabixilol, 33 of which severe, 110 not severe and 5 with no indication of severity. In particular, 5 cases of insomnia have been reported (2 defined not-severe) and 8 cases of drowsiness (not-severe).
1 GPs Local Health and Social Services (ULSS 16), Padova;
2 Pharmaceutical Assistance, Local Health and Social Services (ULSS 16), Padova;
3 Pharmaceutical-Prosthesis-Medical Devices Section, Veneto Region
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