Pharmacokinetics and pharmacodynamics of cannabis-based medicine in a patient population included in a randomized, placebo-controlled, clinical trial.

Information on the pharmacokinetics (PK) and pharmacodynamics (PD) of orally administered cannabis-based medicine (CBM) in capsule formulation in patient populations is sparse. In this exploratory study, we aimed to evaluate the PK and PD in a probable steady state of CBM in neuropathic pain and spasticity in a population of patients with multiple sclerosis (MS). Of 134 patients participating in a randomized, double-blinded, placebo-controlled, trial, 23 patients with MS (17 female) mean age 52 years (range 21-67) were enrolled in this substudy. They received oral capsules containing Δ9 -tetrahydrocannabinol (THC, n = 4), cannabidiol (CBD, n = 6), a combination (THC&CBD, n = 4), or placebo (n = 9). Maximum doses were 22.5 mg (THC) and 45 mg (CBD) a day divided into three administrations. PD parameters were evaluated for pain and spasticity. Blood samples were analyzed using an ultra-high-performance liquid chromatography-tandem mass spectrometer after protein precipitation and phospholipid removal. PK parameters were estimated using computerized modeling. The variation in daily dose and PK between individuals was considerable in a steady state, yet comparable with previous reports from healthy controls. Based on a simulation of the best model, the estimated PK parameters (mean) for THC (5 mg) were Cmax 1.21 ng/mL, Tmax 2.68 h, and half-life 2.75 h, and for CBD (10 mg) were Cmax 2.67 ng/mL, Tmax 0.10 h, and half-life 4.95 h, respectively. No effect was found on the PD parameters, but the placebo response was considerable. More immediate adverse events were registered in the active treatment groups compared with the placebo group.

Cannabis-Based Medicine for Neuropathic Pain and Spasticity-A Multicenter, Randomized, Double-Blinded, Placebo-Controlled Trial.

Patients with multiple sclerosis (MS) and spinal cord injury (SCI) commonly sustain central neuropathic pain (NP) and spasticity. Despite a lack of consistent evidence, cannabis-based medicine (CBM) has been suggested as a supplement treatment. We aimed to investigate the effect of CBM on NP and spasticity in patients with MS or SCI. We performed a randomized, double-blinded, placebo-controlled trial in Denmark. Patients aged ≥18 years with NP (intensity >3, ≤9 on a numerical rating scale (NRS0-10) and/or spasticity (>3 on NRS0-10) were randomized to treatment consisting of either delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), a combination of THC&CBD in maximum doses of 22.5 mg, 45 mg and 22.5/45 mg per day, respectively, or placebo. A baseline registration was performed before randomization. Treatment duration was six weeks followed by a one-week phaseout. Primary endpoints were the intensity of patient-reported NP and/or spasticity. Between February 2019 and December 2021, 134 patients were randomized (MS n = 119, SCI n = 15), where 32 were assigned to THC, 31 to CBD, 31 to THC&CBD, and 40 to placebo. No significant difference was found for: mean pain intensity (THC 0.42 (-0.54-1.38), CBD 0.45 (-0.47-1.38) and THC&CBD 0.16 (-0.75-1.08)), mean spasticity intensity (THC 0.24 (-0.67-1.45), CBD 0.46 (-0.74-1.65), and THC&CBD 0.10 (-1.18-1.39), secondary outcomes (patient global impression of change and quality of life), or any tertiary outcomes. We aimed to include 448 patients in the trial; however, due to COVID-19 and recruitment challenges, fewer were included. Nevertheless, in this four-arm parallel trial, no effect was found between placebo and active treatment with THC or CBD alone or in combination on NP or spasticity in patients with either MS or SCI. The trial was registered with the EU Clinical Trials Register EudraCT (2018-002315-98).

Autonomic dysreflexia and concurrent Horner's Syndrome: a rare presentation in a patient with spinal cord injury.

INTRODUCTION: Autonomic dysreflexia is an uninhibited sympathetic response evoked by a strong sensory input below the level of the injury in patients with spinal cord injury. As presented in this case, autonomic dysreflexia can be associated with unusual symptoms such as Horner's syndrome. CASE PRESENTATION: An 18-year-old man with a traumatic spinal cord injury (C7 AIS A) experienced symptoms of unilateral Horner's syndrome: miosis, ptosis and anhidrosis which occurred simultaneously with symptoms of autonomic dysreflexia: severe headache accompanied by increasing right-sided diaphoresis, flushing, blurred vision, and increased blood pressure. These symptoms were triggered by bladder distention and were resolved after catheterisation. DISCUSSION: The patient experienced a transient Horner's syndrome due to autonomic dysreflexia. Both Horner's syndrome and symptoms of autonomic dysreflexia resolved when eliminating the eliciting stimulus, indicating that Horner's syndrome occurred due to a transient pressure on the sympathetic fibres supplying the superior cervical ganglion. Autonomic dysreflexia may have caused increased pressure disrupting the sympathetic input, thus inducing unilateral miosis, ptosis, and facial anhidrosis.

Autonomic cardiovascular dysfunction during simple arithmetic test in a patient with cervical spinal cord injury-a case report.

INTRODUCTION: Spinal cord injury (SCI) disrupts autonomic control of the cardiovascular system, which may lead to autonomic dysfunction. Growing amounts of evidence support the possibility that systemic and cerebral hemodynamic dysfunctions may contribute to cognitive deficits in patients with SCI. CASE PRESENTATION: We present a case of autonomic cardiovascular dysfunction in a 55-year old female patient following non-traumatic cervical SCI. This case illustrates how a simple arithmetic test may elicit fluctuations in blood pressure causing cognitive disturbances. DISCUSSION: Clinical awareness of autonomic dysfunction and cognitive deficits is relevant in neurorehabilitation of patients with SCI. Assessment of autonomic function should be evaluated according to recommendation from International Standards to document remaining Autonomic Function after Spinal Cord Injury (ISAFSCI) [1].

Postprandial Hypotension and Spinal Cord Injury.

Postprandial hypotension (PPH) is defined as a fall of ≥20 mmHg in systolic blood pressure (SBP) or a SBP of <90 mmHg after having been >100 mmHg before the meal within two hours after a meal. The prevalence of PPH among persons with spinal cord injury (SCI) is unknown. Ambulatory blood pressure measurement was performed in 158 persons with SCI, 109 men, median age was 59.1 years (min.:13.2; max.: 86.2). In total, 78 persons (49.4%) had PPH after 114 out of 449 meals (25.4%). The median change in SBP during PPH was -28 mmHg (min.: -87; max.: -15 mmHg) and 96% of the PPH episodes were asymptomatic. The occurrence of PPH was correlated to older age (p = 0.001), level of injury (p = 0.023), and complete SCI (p = 0.000), but not, gender or time since injury. Further studies are needed to elucidate if PPH contributes to the increased cardiovascular mortality in the SCI population.

The Effect of Cannabis-Based Medicine on Neuropathic Pain and Spasticity in Patients with Multiple Sclerosis and Spinal Cord Injury: Study Protocol of a National Multicenter Double-Blinded, Placebo-Controlled Trial.

Disease or acquired damage to the central nervous system frequently causes disabling spasticity and central neuropathic pain (NP), both of which are frequent in multiple sclerosis (MS) and spinal cord injury (SCI). Patients with MS and SCI often request treatment with cannabis-based medicine (CBM). However, knowledge about effects, side effects, choice of active cannabinoids (Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD) alone or in combination), and doses of CBM remains limited. Using a double-blind, parallel design in a national multicenter cohort, this study examines the effect of CBM on spasticity and NP. Patients are randomized to treatment with capsules containing either THC, CBD, THC and CBD, or placebo. Primary endpoints are patient-reported pain and spasticity on a numerical rating scale. Other endpoints include quality of life and sleep, depression and anxiety, and relief of pain and spasticity. Side-effects of CBM are described. In a sub-study, the pharmacodynamics (PD) and pharmacokinetics (PK) of oral capsule CBM are examined. We expect that the study will contribute to the literature by providing information on the effects and side-effects of CBD, THC, and the combination of the two for central neuropathic pain and spasticity. Furthermore, we will describe the PD/PK of THC and CBD in a patient population.

[Patients with spinal cord injuries experience many sequelae]. / Patienter med rygmarvsskade har mange følgetilstande

Spinal cord injuries (SCI) affect all organs and may cause multiple sequelae. Complications after SCI can be life-threatening and socially disabling. Furthermore, a spinal cord injury is often a chronic condition and the patient may have contact with both the general practitioner and several departments in a hospital. Thus, it is important for all doctors to recognize risks and morbidities related to SCI, in order to prevent and treat the short- and long-term complications and disabilities. This article systematically describes the most commonly encountered sequelae after SCI.