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Central pain in multiple sclerosis: a double-blind placebo-controlled trial of amitriptyline and carbamazepine
Linköping University, Department of Neuroscience and Locomotion, Neurology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Neuroscience and Locomotion, Neurology. Linköping University, Faculty of Health Sciences.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Approximately 23% of all MS patients suffer from non-trigeminal, nonparoxysmal central pain (CP). This pain is generally considered difficult to treat effectively; tricyclic antidepressants, anti epileptic drugs or analgesics are most commonly used. In this study, the pain relieving effects of amitriptyline and carbamazepine were investigated.

The design was a randomised double-blind, three-phase, crossover, placebo-controlled trial. Twenty-three patients with definitive MS entered the study (mean age 55 year, range 40-79 years), all had been thoroughly investigated in a project on CP in MS, and no one showed signs of depression. The treatment phases lasted four weeks, and were separated by a one-week washout. The final doses were 75 mg for amitriptyline and 600 mg for carbamazepine (adjusted from 800 mg, because of side-effects). The effect of treatment was assessed by two daily ratings of pain using a 10- step verbal rating scale (VRS), and at the end of each treatment period using a 5-step global rating scale. For the assessment of depression the Comprehensive Psychopathological Rating Scale (CPRS) was used.

Originally 23 patients were included in the study, but due to side-effects 7 patients discontinued during the amitriptyline phase, and 12 during the carbamazepine phase. With carbamazepine this occurred at low doses (100-200 mg).

The results show that amitriptyline significantly reduced non-paroxysmal CP in MS, compared to placebo (VRS 4.2 vs. 5.3; p<0.05) and according to the global rating; nine of 14 patients were responders (64%). The effect could already be seen during the second week of treatment. The plasma concentrations of amitriptyline and its active metabolite nortriptyline were higher in the responders (329 nmol/l) that in the non-responders (252 nmol/l, n.s). CPRS scores for depression were normal, and were not altered by the medication.

Two of nine patients treated with carbamazepine reported some pain relief, but the effect did not reach significance when compared with placebo. No correlation was found between effect and plasma concentration.

It is concluded that amitriptyline, but not carbamazepine, has a weak effect on non-paroxysmal CP in MS, and that MS patients appear to be particularly sensitive to the side-effects of the two drugs.

National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-81949OAI: oai:DiVA.org:liu-81949DiVA: diva2:556782
Available from: 2012-09-26 Created: 2012-09-26 Last updated: 2012-09-26Bibliographically approved
In thesis
1. Central pain in multiple sclerosis: clinical characteristics, sensory abnormalities and treatment
Open this publication in new window or tab >>Central pain in multiple sclerosis: clinical characteristics, sensory abnormalities and treatment
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In the present research programme the occurrence of pain in MS was investigated, with special emphasis on central pain (CP). Questionnaires were sent to all 429 patients with definite MS in the patient register at our neurology department. All admitting to pain were interviewed by telephone and offered an extended interview and examination at the out patient department. 364 patients replied (86%), of whom 58% reported pain during the course of their disease (21% nociceptive, 2% peripheral neuropathic and 1% related to spasticity). 1 DO patients (27,5%) had CP, including 18 patients (4,9%) with trigeminal neuralgia (TN). Non-trigeminal CP was, in 87%, located in the lower extremities and in 31% in the upper. lt was mostly bilateral (76%) and constant, with 88% experiencing daily pain. Only 2% had paroxysmal attacks. Aching, burning and pricking were the commonest qualities. The pain was intense with little to moderate spontaneous variation. In 5,5% of all patients (20% of the patients with CP), pain was a presenting symptom, alone or in combination with other symptoms. Trigeminal neuralgia in our MS patients started later in life and after longer disease duration than did nontrigeminal pain. Both types of CP existed either chronically or as a feature of relapse.

Somatosensory abnormalities were analysed in detail using traditional neurological tests and quantitative methods for sensory tests (QST) in 62 patients with non-trigeminal CP and in a control group of 16 patients with MS and sensory symptoms, but without pain. 97 per cent of the CP patients had abnormal sensibility to temperature and pain, compared to 81% in the control group (p<0.05), whereas there was a tendency towards the opposite regarding sensibility to touch, which was decreased in 66% vs. 87% (n.s), vibration (81% vs. 55%; n.s) and to joint movement (32% vs. 62%; p<0.04).

Comparison between painful and non-painful regions showed significantly more abnormal sensibility, in the CP regions, for warmth (p<0.001 ), cold (p<0.05), difference limen (innoxious warmth and cold, p<0.01), cold pain (p<0.01), and heat pain/cold pain combined (p<0.001). There were similar differences between CP regions and regions with sensory symptoms, in the controls, for warmth (p<0.05), cold (p<0.01), difference limen (innoxious warmth and cold, p<0.01) and heat pain/cold pain combined (p<0.001).

These results indicate that MS patients with CP have lesions affecting the spinothalamo-cortical pathways (temperature and pain), and that the lesions affect the mediallemniscal pathways (touch, position sense and vibration) to a lesser degree. The opposite was found in the control group.

The results support the general hypothesis that only patients who have lesions affecting the spinothalamo-cortical pathways run the risk of developing CP.

23 MS patients with non-trigeminal CP participated in a double-blind 3-phase, crossover, placebo-controlled study on the pain-relieving effect of amitriptyline and carbamazepine. Each drug was given in randomised order, for a period of 4 weeks, separated by a one-week washout. The target dose was 75 mg for amitriptyline and 600 mg for carbamazepine (reduced from 800 mg because of side-effects). The effect of treatment was assessed by daily ratings of pain using a 10-step verbal rating scale and at the end of each treatment period by a global rating 5-step verbal scale. Due to the high incidence of side-effects 12 and 7 patients discontinued carbamazepine and amitriptyline, respectively. For carbamazepine, these occurred at unexpectedly small doses; 100-200 mg. Amitriptyline, but not carbamazepine, showed a statistically significant pain reduction compared to placebo (p<0.05). According to the global rating, nine of 14 patients were responders. The effect was already noticed during the second week of treatment and it appeared to be correlated to the plasma concentration. Two of 9 patients treated with carbamazepine reported some pain relief, but the effect did not reach statistical significance compared to placebo, and no correlation was found between effect and plasma concentration.

14 opioid-free patients with non-trigeminal CP caused by MS were investigated. Placebo (normal saline), morphine and naloxone were given intravenously in a standardised manner. The design was a non-randomised, single blind, placebo-controlled trial. For pain assessment a visual analogue scale (0-100 mm) was used. Four patients were opioid-responders, i.e. experienced minimal or no effect on pain with placebo, >50% pain reduction after morphine, and >25% pain increase when naloxone was given after morphine. However, the response was obtained only after high doses of morphine (mean 41 mg). Thus, in contrast to nociceptive pain, only a minority of the patients with CP due to MS responded to morphine and only at high doses. These results are in accordance with experimental studies indicating that neuropathic pain is poorly responsive, but not totally unresponsive to opioids.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2005. 62 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 903
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-29988 (URN)15426 (Local ID)91-85299-15-4 (ISBN)15426 (Archive number)15426 (OAI)
Public defence
2005-06-08, Aulan, Hälsans hus, Hälsouniversitetet, Linköping, 13:00 (Swedish)
Opponent
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-09-26Bibliographically approved

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