Tetrahydrocannabinol and cannabidiol as an oromucosal spray in a 1:1 ratio: a therapeutic option for patients with central post-stroke pain syndrome?

Abstract

Background

Some studies have shown that central post-stroke pain (CPSP) syndrome may be more common in patients with lateral medullary syndrome (Wallenberg syndrome), but few cases with such a central pain syndrome are documented worldwide.¹

Treatment of central pain after stroke is difficult and specific guidelines are lacking.² Gabapentin, pregabaline or amitriptyline are options for first-line treatment of central neuropathic pain.³ When medication is ineffective or has intolerable side effects, deep brain stimulation and surgical techniques such as cingulotomy or targeted destruction of a small part of the anterior cingulate cortex are the last option.⁴

Cannabis and its derivatives (cannabinoids) as potential therapeutics especially in inflammatory processes of the central nervous system have been much discussed recently.^{5 6} Clinical studies largely confirm that patients with neuropathic pain benefit from cannabinoid treatment,^{6 7} but clinical value in central pain is shown only in multiple sclerosis studies and not in CPSP syndrome.⁶

Case presentation

A 61-year-old female patient was admitted as an emergency inpatient to a neurological clinic in March 2017 for suspected stroke. She initially had a tendency to fall to the left and weakness of the left leg with ataxic left leg paresis. MRI on the day of admission showed neither fresh cerebral insult nor haemorrhage. The following day, the symptoms worsened. She was unable to stand or walk and showed a marked tendency to fall to the left. The sensation of pain and warmth in the ipsilateral face and contralateral trunk and limbs was impaired. A further MRI now showed a dorsolateral infarction of the left medulla oblongata (figures 1 and 2).

In the inpatient course, the left leg paresis gradually regressed. Directional spontaneous nystagmus with head rotation to the left, diplopia and left-sided Horner’s syndrome developed. Doppler examination of the brain-supplying arteries revealed mild macroangiopathic changes without haemodynamic relevance. Transoesophageal echocardiography showed no evidence of a cardiac source of embolism. Concomitant diseases were arterial hypertension, diet-controlled diabetes mellitus, hypercholesterolaemia and drug-compensated hypothyroidism after strum resection. Cardiovascular risk factors made a microangiopathic aetiology more than likely. Updated drug therapy included acetylsalicylic acid 100 mg and atorvastatin 20 mg. Existing medication with ramipril 5 mg, hydrochlorothiazide 25 mg and L-thyroxine 100 µg was continued. While the neurological symptoms gradually regressed, the patient developed increasing pain 4 weeks after the stroke, which reached its maximum after 8 weeks. The burning, electrifying, tingling continuous pain in the right leg scored 8–9 out of 10 on the Numerical Rating Scale (NRS) for pain. At the same time, the patient developed burning, stabbing, sometimes spontaneously shooting pain in the left side of her face in the first and second trigeminal branches of somewhat lower intensity (average 6 out of 10 points in the NRS), aggravated by cold (figure 3).

Treatment

Therapeutic attempts over more than 3 years with amitriptyline, gabapentin, pregabalin and various level II and III opioids were ineffective or showed intolerable side effects.

This was the reason why the patient eventually saw a pain management specialist (UM).

The analysis of the pain situation, pain quality and quality of life was initially carried out with the German Pain Questionnaire,⁸ and a modified German version of the ‘short pain inventory’⁹ was used for control examinations. Both a combination of calcium modulators and tricyclic antidepressants and a switch of the level III opioid to hydromorphone did not provide sufficient improvement. Therefore, a therapy trial with nabiximols (Sativex) was undertaken at the end of July 2020.

Outcome and follow-up

Two days later, the patient reported by telephone a marked improvement in perceived pain intensity, daily activity, mood, sleep and general quality of life under 2×1 sprays of nabiximols (figure 4). An agreement was made with the patient to adjust the dose of nabiximols to the current pain situation and to increase it as needed. Following this suggestion, she was able to slowly discontinue the previous pain medication without noticing a worsening of her symptoms. This positive effect continues to this day at a dosage of 6 sprays of nabiximols daily (Tetrahydrocannabinol: 16.2 mg and Cannabidiol: 15.0 mg). No accompanying analgesic or coanalgesic treatment is required. The patient has consistently rated the average pain intensity as 3–4 out of 10 points on the NRS since August 2020 and the restriction of quality of life (general activity, restriction of enjoyment of life and restriction of sleep quality) as 1–3 out of 10 points on the NRS (figure 4). She reported neither side effects nor development of tolerance during an observation period of now 10 months.

Discussion

Ischaemic stroke is not only a vascular disease but also many neural and vascular cells (microglia, macrophages, astrocytes, neurons and endothelial cells) as well as complex cellular and molecular cascades are involved in this process.¹⁰

Why and under what circumstances pain after stroke may occur remains unclear. Central disinhibition, central sensitisation, thalamic changes and inflammatory responses of the involved neural pathways are frequently discussed aetiological and pathophysiological theories.⁴ Only when parts of the sensory pathways remain partially intact does maladaptive synaptic reorganisation of the neuronal circuits apparently leads to changes in pain processing and, therefore, CPSP syndrome occurs almost exclusively in patients in whom the spinothalamic tract is only partially damaged,¹¹ as in the present case (see figure 1).

A stroke lesion consists of an ischaemic core and the surrounding penumbra, with irreversible cell death occurring mainly in the ischaemic core region. The development of a CPSP syndrome seems to be quite significantly related to reperfusion injury in the penumbra region.¹² Reoxygenation can cause secondary damage through the excessive formation of reactive radical oxygen species (ROS), peroxynitrite and immune system activation, which overwhelm the endogenous antioxidant capacity of ischaemic brain cells.¹³ Reperfusion injury further leads to activation of the brain’s endogenous immune cells, microglia and ischaemic endothelium.¹⁴ Circulating leucocytes colonise in areas of activated endothelia and bind adhesion molecules that promote penetration into the ischaemic tissue. Once leucocytes and activated microglia infiltrate ischaemic brain tissue, they produce various proinflammatory molecules, such as chemokines, complement, cytokines, inducible nitric oxide synthase and even more ROS.¹⁴ Immunoreactive cells, particularly astrocytes, can release chondroitin sulfate proteoglycans (inhibitory extracellular molecules), leading to hypertrophy, preventing normal axonal regeneration and promoting sprouting. In addition to the resulting glial scar, myelin (the laminated membrane structure surrounding the axon) is also partly responsible for the failure of axonal regeneration, which can lead to ephaptic transmission of abnormal electrical impulses with corresponding pain sensations.^{15 16}

All these complex damages can lead to maladaptive neuroplastic processes as a basis for the development of CPSP syndrome.

The question arises whether the mechanism of action of cannabinoids can plausibly explain such a marked and sustained improvement in the present case. The anti-inflammatory, antioxidant and anti-apoptotic effects of cannabinoids have long been recognised.¹⁷ Cannabinoid receptor agonists reduce microglial and macrophage activation after induction of ischaemia in mice and rats, resulting in reduced infarct size and neurological impairment and protection of oligodendrocyte progenitor cells.¹⁸ They can also reduce the concentration of glutamate-derived metabolites in both cortical and subcortical brain areas.¹⁹

Tetrahydrocannabinol (THC) acts on at least two types of receptors found in mammals, cannabinoid 1 (CB1) and cannabinoid 2 (CB2). CB1 receptors (CB1Rs) are located predominantly in central and peripheral neurons, where they modulate the release of neurotransmitters. They are distributed throughout the nervous system and mediate psychoactivity, pain regulation, memory processing and motor control.²⁰ THC suppresses synaptic transmission of glutamate via CB1R activation, reduces glutamate release and inhibits receptor and transporter function.⁶ In both animal models and clinical studies, agonists at CB1R have shown an effect on chronic neuropathic pain.^{13 21} The type 2 cannabinoid receptor (CB2R) was initially regarded as a peripheral receptor. Recent technological advances in gene detection indicate that CB2Rs are expressed in both neurons and glial cells in the brain under physiological and pathological conditions and are involved in multiple functions at the cellular and molecular levels.²⁰ CB2R levels in the brain of healthy humans are low under basal conditions, but are inducible or can be upregulated in response to various noxious agents, including chronic pain and ischaemia-induced hypoxia.²² The upregulation of CB2Rs in the brain may be due to a neuroprotective response in various central nervous system injuries. Activation of CB2R inhibits spontaneous and evoked neuronal responses to noxious stimuli in the dorsal root ganglia, spinal cord and thalamus.²³ The inhibitory effect of CB2 on the activation of different subpopulations of microglia and macrophages may explain the protective effect of selective CB2R agonists after stroke.²⁴ The positive effect of cannabinoids in ischaemic stroke is confirmed in several clinical studies.²⁵

Cannabidiol (CBD), the second main component of nabiximols used in the present case, has shown a wide range of therapeutic properties in many preclinical studies. CBD has proven anxiolytic,²⁶ neuroprotective,^27–29 antidepressant,³⁰ anti-inflammatory^{30 31} and immunomodulatory effects^{32 33} in these studies. CBD’s neuroprotective effects are mainly attributed to its antioxidant and anti-inflammatory activities and modulation of a variety of biological targets in the brain, such as receptors and channels involved in the development and maintenance of neurological diseases.³⁴ In animal studies with artificially induced cerebral ischaemia, CBD displayed a reduction in cerebral oedema and blood–brain barrier permeability, trends towards infarct reduction, improved functional outcomes and had higher survival rates.^35–38 Although human research with double-blind randomised controlled trials is still largely lacking, there is much preclinical evidence and theoretical basis to support the idea of using CBD for its neuroprotective properties in cerebral ischaemia.^39–41 In a recent critical clinical review, only the combination of THC and CBD in a 1:1 ratio showed a convincing and clinically relevant effect on neuropathic pain.⁴² This was the reason for choosing the aforementioned combination of THC and CBD in the present case, as peripheral neuropathic pain and central pain probably have similar neurobiological mechanisms.⁴³

To the best of our knowledge, for efficacy of cannabis in central pain other than Multiple Sclerosis, there is only one case report⁴⁴ and systematic, more comprehensive studies are lacking.

The encouraging outcome in the patient presented here should encourage us to consider treatment with cannabis in a 1:1 ratio of THC and CBD in CPSP syndrome when standard therapies are not sufficient.

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