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  • 1.
    Kalman, Sigga
    et al.
    Linköping University, Department of Medicine and Care, Anaesthesiology. Linköping University, Faculty of Health Sciences.
    Österberg, Anders
    Linköping University, Department of Neuroscience and Locomotion, Neurology. Linköping University, Faculty of Health Sciences.
    Sörensen, Jan
    Linköping University, Department of Medicine and Care, Anaesthesiology. Linköping University, Faculty of Health Sciences.
    Boivie, Jörgen
    Linköping University, Department of Neuroscience and Locomotion, Neurology. Linköping University, Faculty of Health Sciences.
    Bertler, Åke
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Morphine responsiveness in a group of well-defined multiple sclerosis patients: a study with i.v. morphine2002In: European Journal of Pain, ISSN 1090-3801, E-ISSN 1532-2149, Vol. 6, no 1, p. 69-80Article in journal (Refereed)
    Abstract [en]

    Pain in multiple sclerosis (MS) is more common than has previously been believed. About 28% of all MS patients suffer from central pain (CP), a pain that is difficult to treat. In the present study we have investigated the responsiveness of this pain to morphine. Fourteen opioid-free patients (eight woman and six men) with constant, non-fluctuating, long-lasting CP caused by MS were investigated. Placebo (normal saline), morphine and naloxone were given intravenously in a standardized manner. The study design was non-randomized, single blind and placebo controlled. Ten patients experienced less than 50% pain reduction by placebo and less than 50% pain reduction by morphine. Four patients were opioid responders, i.e. had minimal or no effect on pain by placebo, >50% pain reduction after morphine and >25% pain increase after naloxone, given intravenously following morphine. However, this response was obtained after high doses of morphine (43 mg, 47 mg, 50 mg and 25 mg; mean 41 mg). Thus, compared with nociceptive pain, only a minority of the patients with CP due to MS responded to morphine and only at high doses. The present results are in accord with experimental studies indicating that neuropathic pain is poorly responsive but not totally unresponsive to opioids. The results do not support the routine use of strong opioids in MS patients with CP.

  • 2.
    Österberg, Anders
    Linköping University, Department of Neuroscience and Locomotion, Neurology. Linköping University, Faculty of Health Sciences.
    Central pain in multiple sclerosis: clinical characteristics, sensory abnormalities and treatment2005Doctoral 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.

    List of papers
    1. Central pain in multiple sclerosis: prevalence and clinical characteristics
    Open this publication in new window or tab >>Central pain in multiple sclerosis: prevalence and clinical characteristics
    2005 (English)In: European Journal of Pain, ISSN 1090-3801, E-ISSN 1532-2149, Vol. 9, no 5, p. 531-542Article in journal (Refereed) Published
    Abstract [en]

    Pain is more common in multiple sclerosis (MS) than has previously been recognised. In the present study we have investigated the occurrence of central pain (CP) in MS and defined its characteristics. Questionnaires were sent to all 429 patients with definite MS in the patient register at our neurology department. All admitting to pain were interviewed and offered an extended interview and examination. Three hundred and sixty four patients responded (86%), of whom 57.5% reported pain during the course of their disease (21% nociceptive, 2% peripheral neuropathic and 1% related to spasticity). One hundred patients (27.5%) had CP, including 18 patients (4.9%) with trigeminal neuralgia.

    The non-trigeminal CP was, in 87%, located in the lower and in 31% in the upper extremities. It was mostly bilateral (76%) and constant, with 88% experiencing daily pain. Only 2% had paroxysmal attacks. Aching, burning, pricking were the commonest qualities. The pain was intense with small 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.

    The most common neurological symptoms/signs besides CP were sensory abnormalities (98%, dominated by abnormal sensibility to painful stimulus and temperature). Trigeminal neuralgia in MS started later in life and after longer disease duration than non-trigeminal pain. Both types of CP existed either chronically or as a feature of relapse. Central pain is thus an important symptom in MS (around 30%) and causes much suffering.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-31877 (URN)10.1016/j.ejpain.2004.11.005 (DOI)17705 (Local ID)17705 (Archive number)17705 (OAI)
    Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2017-12-13Bibliographically approved
    2. Central pain in multiple sclerosis: sensory abnormalities
    Open this publication in new window or tab >>Central pain in multiple sclerosis: sensory abnormalities
    2010 (English)In: European Journal of Pain, ISSN 1090-3801, E-ISSN 1532-2149, Vol. 14, no 1, p. 104-110Article in journal (Refereed) Published
    Abstract [en]

    Many patients with multiple sclerosis (MS) develop central neuropathic pain (CP). In the present study somatosensory abnormalities have been analysed in detail in 62 patients with MS and CP (42 women, 20 men; mean age 52 years) and in a control group of 10 women and 6 men (mean age 47 years) with MS and sensory symptoms, but without pain.

    Assessment included clinical testing and quantitative methods (QST) for the measurement of perception thresholds for touch, vibration, and temperatures.

    All CP patients except two (97%) had abnormal thresholds for innoxious and/or noxious temperatures, compared to 81% in the control group (p < 0.05). There was a tendency towards the opposite regarding sensibility to touch, which was decreased in 66% vs. 87% (n.s.), vibration (55% vs. 81%; n.s.) and to joint movement (32% vs. 62%; p < 0.04).

    Comparisons between painful and non-painful regions showed both the absolute threshold values and the index values to be significantly more abnormal, 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).

    Also the comparisons between regions with central pain and regions with sensory symptoms in the controls showed significantly more abnormal thresholds in the CP patients 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).

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

    Keywords
    Multiple sclerosis, Central neuropathic pain, Sensibility, Quantitative sensory test (QST)
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-54155 (URN)10.1016/j.ejpain.2009.03.003 (DOI)000274481800017 ()
    Available from: 2010-02-26 Created: 2010-02-26 Last updated: 2017-12-12Bibliographically approved
    3. Central pain in multiple sclerosis: a double-blind placebo-controlled trial of amitriptyline and carbamazepine
    Open this publication in new window or tab >>Central pain in multiple sclerosis: a double-blind placebo-controlled trial of amitriptyline and carbamazepine
    (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:nbn:se:liu:diva-81949 (URN)
    Available from: 2012-09-26 Created: 2012-09-26 Last updated: 2012-09-26Bibliographically approved
    4. Morphine responsiveness in a group of well-defined multiple sclerosis patients: a study with i.v. morphine
    Open this publication in new window or tab >>Morphine responsiveness in a group of well-defined multiple sclerosis patients: a study with i.v. morphine
    Show others...
    2002 (English)In: European Journal of Pain, ISSN 1090-3801, E-ISSN 1532-2149, Vol. 6, no 1, p. 69-80Article in journal (Refereed) Published
    Abstract [en]

    Pain in multiple sclerosis (MS) is more common than has previously been believed. About 28% of all MS patients suffer from central pain (CP), a pain that is difficult to treat. In the present study we have investigated the responsiveness of this pain to morphine. Fourteen opioid-free patients (eight woman and six men) with constant, non-fluctuating, long-lasting CP caused by MS were investigated. Placebo (normal saline), morphine and naloxone were given intravenously in a standardized manner. The study design was non-randomized, single blind and placebo controlled. Ten patients experienced less than 50% pain reduction by placebo and less than 50% pain reduction by morphine. Four patients were opioid responders, i.e. had minimal or no effect on pain by placebo, >50% pain reduction after morphine and >25% pain increase after naloxone, given intravenously following morphine. However, this response was obtained after high doses of morphine (43 mg, 47 mg, 50 mg and 25 mg; mean 41 mg). Thus, compared with nociceptive pain, only a minority of the patients with CP due to MS responded to morphine and only at high doses. The present results are in accord with experimental studies indicating that neuropathic pain is poorly responsive but not totally unresponsive to opioids. The results do not support the routine use of strong opioids in MS patients with CP.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-26814 (URN)10.1053/eujp.2001.0307 (DOI)11425 (Local ID)11425 (Archive number)11425 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
  • 3.
    Österberg, Anders
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Neurology. Linköping University, Faculty of Health Sciences.
    Boivie, Jörgen
    Linköping University, Department of Neuroscience and Locomotion, Neurology. Linköping University, Faculty of Health Sciences.
    Central pain in multiple sclerosis: a double-blind placebo-controlled trial of amitriptyline and carbamazepineManuscript (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.

  • 4.
    Österberg, Anders
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Neurology. Linköping University, Faculty of Health Sciences.
    Boivie, Jörgen
    Linköping University, Department of Clinical and Experimental Medicine, Neurology. Linköping University, Faculty of Health Sciences.
    Central pain in multiple sclerosis: sensory abnormalities2010In: European Journal of Pain, ISSN 1090-3801, E-ISSN 1532-2149, Vol. 14, no 1, p. 104-110Article in journal (Refereed)
    Abstract [en]

    Many patients with multiple sclerosis (MS) develop central neuropathic pain (CP). In the present study somatosensory abnormalities have been analysed in detail in 62 patients with MS and CP (42 women, 20 men; mean age 52 years) and in a control group of 10 women and 6 men (mean age 47 years) with MS and sensory symptoms, but without pain.

    Assessment included clinical testing and quantitative methods (QST) for the measurement of perception thresholds for touch, vibration, and temperatures.

    All CP patients except two (97%) had abnormal thresholds for innoxious and/or noxious temperatures, compared to 81% in the control group (p < 0.05). There was a tendency towards the opposite regarding sensibility to touch, which was decreased in 66% vs. 87% (n.s.), vibration (55% vs. 81%; n.s.) and to joint movement (32% vs. 62%; p < 0.04).

    Comparisons between painful and non-painful regions showed both the absolute threshold values and the index values to be significantly more abnormal, 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).

    Also the comparisons between regions with central pain and regions with sensory symptoms in the controls showed significantly more abnormal thresholds in the CP patients 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).

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

  • 5.
    Österberg, Anders
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Neurology. Linköping University, Faculty of Health Sciences.
    Boivie, Jörgen
    Linköping University, Department of Neuroscience and Locomotion, Neurology. Linköping University, Faculty of Health Sciences.
    Thoumas, K-Å
    Linköping University, Department of Medicine and Care, Radiology. Linköping University, Faculty of Health Sciences.
    Central pain in multiple sclerosis: prevalence and clinical characteristics2005In: European Journal of Pain, ISSN 1090-3801, E-ISSN 1532-2149, Vol. 9, no 5, p. 531-542Article in journal (Refereed)
    Abstract [en]

    Pain is more common in multiple sclerosis (MS) than has previously been recognised. In the present study we have investigated the occurrence of central pain (CP) in MS and defined its characteristics. Questionnaires were sent to all 429 patients with definite MS in the patient register at our neurology department. All admitting to pain were interviewed and offered an extended interview and examination. Three hundred and sixty four patients responded (86%), of whom 57.5% reported pain during the course of their disease (21% nociceptive, 2% peripheral neuropathic and 1% related to spasticity). One hundred patients (27.5%) had CP, including 18 patients (4.9%) with trigeminal neuralgia.

    The non-trigeminal CP was, in 87%, located in the lower and in 31% in the upper extremities. It was mostly bilateral (76%) and constant, with 88% experiencing daily pain. Only 2% had paroxysmal attacks. Aching, burning, pricking were the commonest qualities. The pain was intense with small 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.

    The most common neurological symptoms/signs besides CP were sensory abnormalities (98%, dominated by abnormal sensibility to painful stimulus and temperature). Trigeminal neuralgia in MS started later in life and after longer disease duration than non-trigeminal pain. Both types of CP existed either chronically or as a feature of relapse. Central pain is thus an important symptom in MS (around 30%) and causes much suffering.

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