Pain research & management : the journal of the Canadian Pain Society = journal de la société canadienne pour le traitement de la douleur, 2002
Chronic pain is one of the most common reasons for therapeutic cannabis use. To describe therapeu... more Chronic pain is one of the most common reasons for therapeutic cannabis use. To describe therapeutic cannabis use among patients with chronic pain. Patients with chronic pain who voluntarily indicated that they used cannabis therapeutically completed a questionnaire about the type of cannabis used, the mode of administration, the amount used and the frequency of use, and their perception of the effectiveness of cannabis on a set of pain-associated symptoms and side effects. The study was approved by the McGill University Health Centre Research Ethics Board. Fifteen patients (10 male) were interviewed (median age 49.5 years, range 24 to 68 years). All patients smoked herbal cannabis for therapeutic reasons (median duration of use six years, range two weeks to 37 years). Seven patients only smoked at night-time (median dose eight puffs, range two to eight puffs), and eight patients used cannabis mainly during the day (median dose three puffs, range two to eight puffs); the median freq...
Objective Patients with osteoarthritis (OA) pain often have insufficient pain relief from non-opi... more Objective Patients with osteoarthritis (OA) pain often have insufficient pain relief from non-opioid analgesics. The aim of this trial was to study efficacy and tolerability of a low dose 7-day buprenorphine transdermal delivery system, added to a NSAID or coxib regimen, in opioid-naïve patients with moderate to severe OA pain. Methods A 6 months randomised, double-blind, parallel-group study at 19 centres in Denmark, Finland, Norway, and Sweden, in which OA patients (>40 years) with at least moderate radiographic OA changes and at least moderate pain in a hip and/or knee while on a NSAID or a coxib were randomised to a 7-day buprenorphine patch (n = 100) or an identical placebo patch (n = 99). The initial patch delivered buprenorphine 5 μg/h. This was titrated to 10 or 20 μg/h, as needed. Rescue analgesic was paracetamol 0.5–4 g daily. Statistical analysis of outcome data was mainly with a general linear model, with treatment as factor, the primary joint of osteoarthritis, basel...
Plasma concentrations, maximum regional brain concentrations, and specific regional binding in th... more Plasma concentrations, maximum regional brain concentrations, and specific regional binding in the brain after administration of 0, 0.1, and 0.2 mg/kg doses of (S)-ketamine were measured in a randomized, double-blind, crossover study in five volunteers and were related to induced effects such as analgesia, amnesia, and mood changes. Specific binding in the brain was assessed by simultaneous administration of (S)-[N-methyl-11C]ketamine quantified by positron emission tomography. High radioactivities in the brain corresponded to regional distribution of N-methyl-D-aspartate receptor complexes. A significant and dose-dependent reduction of binding was measured as a result of displacement of (S)-[N-methyl-11C]ketamine. Memory impairment and psychotomimetic effects were related to dose, plasma concentration 4 minutes after administration, and decreased regional binding of (S)-ketamine in the brain and were consistently seen at plasma and maximum regional brain (S)-ketamine concentrations higher than 70 and 500 ng/ml, respectively. The magnitude of specific binding of (S)-ketamine, measured with positron emission tomography, can be related directly to drug effects.
Evidence suggests that NMDA receptors may have a differential role in the modulation of visceral ... more Evidence suggests that NMDA receptors may have a differential role in the modulation of visceral and somatic pain. Specifically, animal data indicate an analgesic role of NMDA-R antagonists in acute visceral but not acute somatic pain. In humans analgesic effects are documented in acute somatic pain, while the role of NMDA-R antagonists in acute visceral pain is still questionable. We, therefore, conducted a study in humans comparing the analgesic effects of ketamine in an experimental model of visceral and cutaneous pain. In a double-blind, randomized, cross-over study, 11 healthy volunteers (3M, 8F) participated in two experimental sessions in which they evaluated perceptions induced by balloon distention of the distal esophagus and contact heat on the upper chest during continuous computer-controlled i.v. infusion of either ketamine (60 and 120 ng/mL) or saline. Two stimulus intensities producing non-painful and painful sensation were used for each stimulus modality. Subjects reported maximum pain intensity and unpleasantness on visual analog scales (VAS). For noxious visceral stimulation, low dose ketamine produced significant attenuation of both pain intensity and unpleasantness. In contrast, for noxious cutaneous stimulation, ketamine reduced pain unpleasantness, but not perceived intensity. In addition, ketamine did not alter the perception of innocuous stimuli in either modality. Our results confirm the analgesic effects of low-dose ketamine, with minimal side effects, on acute visceral pain and indicate a similar but smaller effect on acute cutaneous pain. A decrease in the unpleasantness but not in the intensity of cutaneous pain may reflect the differential effect of NMDA-R antagonists for the two pain states observed in animal models.
Allodynia is a well-known component of neuropathic pain resulting from injury to the nervous syst... more Allodynia is a well-known component of neuropathic pain resulting from injury to the nervous system. Clinical pain states with allodynia in connection with longstanding superficial wounds have, however, not been reported in the literature. In this case a chronic pain state developed in a previously healthy 17-year-old girl in and around a persistently suppurating appendectomy wound. There was no spontaneous pain but pronounced allodynia in the wound and in the surrounding skin. Quantitative thermal tests showed abnormal thresholds for several sensory modalities confirming abnormal processing of sensory input from the involved area. The pattern of sensory abnormalities evaluated with thermal testing changed transiently and the allodynia diminished during a phentolamine block. Since the pain responded poorly to opioids and ketamine has been reported to reduce allodynia, it was administered in a sub-dissociative bolus dose during wound dressing. The wound was essentially unchanged after treatment for 3 months but the allodynia and sensory aberrations had decreased significantly. We interpret these results as a de-sensitizing effect in the long term of repeated NMDA-receptor blockade by ketamine in a chronic pain state, with indications of central sensitization, partially maintained by sympathetic activity.
There is a growing interest in low-dose ketamine as an analgesic agent in different intractable p... more There is a growing interest in low-dose ketamine as an analgesic agent in different intractable pain conditions. Due to its narrow therapeutic window, well-defined pharmacokinetic parameters are essential for its successful use in these situations. Arterial data for ketamine or its enantiomers have not been reported before. The metabolic pathways involved in the metabolism of S- and R-ketamines are not known. Ten healthy male volunteers received 7 mg infusions of R- and S-ketamine-hydrochloride in a randomised order over 30 min on 2 separate days. Six were extensive metabolisers, two were poor metabolisers of debrisoquine (CYP2D6) and two were poor metabolisers of mephenytoin (CYP2C19). Arterial and venous concentrations and non-analgesic side effects were measured. Subjective side effects were mild but more pronounced for S- than for R-ketamine. There were no salient differences between the subjects with reduced and normal metabolic capacity in pharmacokinetic parameters or in side effects. Volumes of distribution and mean residence times were 40% smaller for arterial than for venous data. The mean clearance of R-ketamine, 0.020 l min(-1) kg(-1), was slightly but significantly lower than of S-ketamine, 0.024 l min(-1) kg(-1). There are large differences between arterial and venous data in the pharmacokinetic parameters that are heavily dependent on distribution processes. Parameters mainly reflecting elimination, such as clearance and area under the concentration time curve, are unchanged. The choice of sampling site could be important when computer-controlled infusions are used.
Ketamine has been repeatedly reviewed in this journal but novel developments have occurred in the... more Ketamine has been repeatedly reviewed in this journal but novel developments have occurred in the last few years prompting an update. Interesting recent publications will be highlighted against a background of established knowledge. In the field of anesthesia, particularly in pediatrics, some contributions have been made concerning intramuscular versus intravenous induction. The need for anticholinergic adjuvants has also been clarified. Neuroapoptosis has been observed in animals and its implications for human subjects are discussed in a general context of neurotoxicity. The most important developments, however, are in the treatment of pain. Neurological and urological side effects strongly question long-term use. Other potentially beneficial effects have also been reported, such as anti-inflammatory and antidepressive effects. There are also indications that ketamine may attenuate postoperative delirium in coronary by-pass patients. More questions have arisen than have been answered. Some have very grave implications. The issue of neuroapoptosis must be clarified. The long-term effects must be further investigated. On the bright side the effects on postoperative delirium, as well as the anti-inflammatory and antidepressive effects, might open new vistas for an old drug.
For ketamine&... more For ketamine's fiftieth birthday, a narrative review of this unique drug in pain management is presented. Its history is traced from its conception, and its heritage, as a phencyclidine offspring, delineated. The earliest roots of the conceptions concerning the mechanisms of action are sought, and then followed in preclinical as well as clinical research. The major proposed mechanisms in the literature are commented on and evaluated. The growth of the clinical evidence for perioperative pain, acute pain, and chronic pain is followed from early attempts to systematic reviews. Finally, an attempt is made to foresee what the next 50 years might hold in store for our 50 years old.
Ketamine in sub-dissociative doses has been shown to have analgesic effects in various pain condi... more Ketamine in sub-dissociative doses has been shown to have analgesic effects in various pain conditions, including neuropathic and phantom-limb pain, where conventional treatment has often failed. Chronic ischemic pain due to lower extremity arteriosclerosis obliterans often responds poorly to analgesics, and the pain-generating mechanisms are not well understood. Eight patients with rest pain in the lower extremity due to arteriosclerosis obliterans were given sub-dissociative doses of 0.15, 0.30, or 0.45 mg/kg racemic ketamine and morphine 10 mg as a 5-min infusion on four separate days in a cross-over, double-blind, randomised protocol. Plasma levels of (S)- and (R)-ketamine and their nor-metabolites were analysed with an enantioselective high-performance liquid chromatography (HPLC) method. Pain levels were evaluated with a visual analogue scale (VAS). Individual pain levels were highly variable during and after all the infusions but the pooled pain levels showed a dose-dependent analgesic effect of ketamine with a transient but complete pain relief in all the patients at the highest dose (0.45 mg/kg). Side-effects, mainly disturbed cognition and perception, were pronounced and dose-dependent. Morphine 10 mg had an analgesic peak at 20 min and 5/8 patients had complete pain relief. These 3 patients also had high baseline pain scores, indicating a higher analgesic potency for the 0.30 and 0.45 mg/kg ketamine doses than for morphine 10 mg. We have demonstrated a potent dose-dependent analgesic effect of racemic ketamine in clinical ischemic pain. Due to a narrow therapeutic window, this analgesic effect is probably best utilised in combination with other analgesics.
Pain research & management : the journal of the Canadian Pain Society = journal de la société canadienne pour le traitement de la douleur, 2002
Chronic pain is one of the most common reasons for therapeutic cannabis use. To describe therapeu... more Chronic pain is one of the most common reasons for therapeutic cannabis use. To describe therapeutic cannabis use among patients with chronic pain. Patients with chronic pain who voluntarily indicated that they used cannabis therapeutically completed a questionnaire about the type of cannabis used, the mode of administration, the amount used and the frequency of use, and their perception of the effectiveness of cannabis on a set of pain-associated symptoms and side effects. The study was approved by the McGill University Health Centre Research Ethics Board. Fifteen patients (10 male) were interviewed (median age 49.5 years, range 24 to 68 years). All patients smoked herbal cannabis for therapeutic reasons (median duration of use six years, range two weeks to 37 years). Seven patients only smoked at night-time (median dose eight puffs, range two to eight puffs), and eight patients used cannabis mainly during the day (median dose three puffs, range two to eight puffs); the median freq...
Objective Patients with osteoarthritis (OA) pain often have insufficient pain relief from non-opi... more Objective Patients with osteoarthritis (OA) pain often have insufficient pain relief from non-opioid analgesics. The aim of this trial was to study efficacy and tolerability of a low dose 7-day buprenorphine transdermal delivery system, added to a NSAID or coxib regimen, in opioid-naïve patients with moderate to severe OA pain. Methods A 6 months randomised, double-blind, parallel-group study at 19 centres in Denmark, Finland, Norway, and Sweden, in which OA patients (>40 years) with at least moderate radiographic OA changes and at least moderate pain in a hip and/or knee while on a NSAID or a coxib were randomised to a 7-day buprenorphine patch (n = 100) or an identical placebo patch (n = 99). The initial patch delivered buprenorphine 5 μg/h. This was titrated to 10 or 20 μg/h, as needed. Rescue analgesic was paracetamol 0.5–4 g daily. Statistical analysis of outcome data was mainly with a general linear model, with treatment as factor, the primary joint of osteoarthritis, basel...
Plasma concentrations, maximum regional brain concentrations, and specific regional binding in th... more Plasma concentrations, maximum regional brain concentrations, and specific regional binding in the brain after administration of 0, 0.1, and 0.2 mg/kg doses of (S)-ketamine were measured in a randomized, double-blind, crossover study in five volunteers and were related to induced effects such as analgesia, amnesia, and mood changes. Specific binding in the brain was assessed by simultaneous administration of (S)-[N-methyl-11C]ketamine quantified by positron emission tomography. High radioactivities in the brain corresponded to regional distribution of N-methyl-D-aspartate receptor complexes. A significant and dose-dependent reduction of binding was measured as a result of displacement of (S)-[N-methyl-11C]ketamine. Memory impairment and psychotomimetic effects were related to dose, plasma concentration 4 minutes after administration, and decreased regional binding of (S)-ketamine in the brain and were consistently seen at plasma and maximum regional brain (S)-ketamine concentrations higher than 70 and 500 ng/ml, respectively. The magnitude of specific binding of (S)-ketamine, measured with positron emission tomography, can be related directly to drug effects.
Evidence suggests that NMDA receptors may have a differential role in the modulation of visceral ... more Evidence suggests that NMDA receptors may have a differential role in the modulation of visceral and somatic pain. Specifically, animal data indicate an analgesic role of NMDA-R antagonists in acute visceral but not acute somatic pain. In humans analgesic effects are documented in acute somatic pain, while the role of NMDA-R antagonists in acute visceral pain is still questionable. We, therefore, conducted a study in humans comparing the analgesic effects of ketamine in an experimental model of visceral and cutaneous pain. In a double-blind, randomized, cross-over study, 11 healthy volunteers (3M, 8F) participated in two experimental sessions in which they evaluated perceptions induced by balloon distention of the distal esophagus and contact heat on the upper chest during continuous computer-controlled i.v. infusion of either ketamine (60 and 120 ng/mL) or saline. Two stimulus intensities producing non-painful and painful sensation were used for each stimulus modality. Subjects reported maximum pain intensity and unpleasantness on visual analog scales (VAS). For noxious visceral stimulation, low dose ketamine produced significant attenuation of both pain intensity and unpleasantness. In contrast, for noxious cutaneous stimulation, ketamine reduced pain unpleasantness, but not perceived intensity. In addition, ketamine did not alter the perception of innocuous stimuli in either modality. Our results confirm the analgesic effects of low-dose ketamine, with minimal side effects, on acute visceral pain and indicate a similar but smaller effect on acute cutaneous pain. A decrease in the unpleasantness but not in the intensity of cutaneous pain may reflect the differential effect of NMDA-R antagonists for the two pain states observed in animal models.
Allodynia is a well-known component of neuropathic pain resulting from injury to the nervous syst... more Allodynia is a well-known component of neuropathic pain resulting from injury to the nervous system. Clinical pain states with allodynia in connection with longstanding superficial wounds have, however, not been reported in the literature. In this case a chronic pain state developed in a previously healthy 17-year-old girl in and around a persistently suppurating appendectomy wound. There was no spontaneous pain but pronounced allodynia in the wound and in the surrounding skin. Quantitative thermal tests showed abnormal thresholds for several sensory modalities confirming abnormal processing of sensory input from the involved area. The pattern of sensory abnormalities evaluated with thermal testing changed transiently and the allodynia diminished during a phentolamine block. Since the pain responded poorly to opioids and ketamine has been reported to reduce allodynia, it was administered in a sub-dissociative bolus dose during wound dressing. The wound was essentially unchanged after treatment for 3 months but the allodynia and sensory aberrations had decreased significantly. We interpret these results as a de-sensitizing effect in the long term of repeated NMDA-receptor blockade by ketamine in a chronic pain state, with indications of central sensitization, partially maintained by sympathetic activity.
There is a growing interest in low-dose ketamine as an analgesic agent in different intractable p... more There is a growing interest in low-dose ketamine as an analgesic agent in different intractable pain conditions. Due to its narrow therapeutic window, well-defined pharmacokinetic parameters are essential for its successful use in these situations. Arterial data for ketamine or its enantiomers have not been reported before. The metabolic pathways involved in the metabolism of S- and R-ketamines are not known. Ten healthy male volunteers received 7 mg infusions of R- and S-ketamine-hydrochloride in a randomised order over 30 min on 2 separate days. Six were extensive metabolisers, two were poor metabolisers of debrisoquine (CYP2D6) and two were poor metabolisers of mephenytoin (CYP2C19). Arterial and venous concentrations and non-analgesic side effects were measured. Subjective side effects were mild but more pronounced for S- than for R-ketamine. There were no salient differences between the subjects with reduced and normal metabolic capacity in pharmacokinetic parameters or in side effects. Volumes of distribution and mean residence times were 40% smaller for arterial than for venous data. The mean clearance of R-ketamine, 0.020 l min(-1) kg(-1), was slightly but significantly lower than of S-ketamine, 0.024 l min(-1) kg(-1). There are large differences between arterial and venous data in the pharmacokinetic parameters that are heavily dependent on distribution processes. Parameters mainly reflecting elimination, such as clearance and area under the concentration time curve, are unchanged. The choice of sampling site could be important when computer-controlled infusions are used.
Ketamine has been repeatedly reviewed in this journal but novel developments have occurred in the... more Ketamine has been repeatedly reviewed in this journal but novel developments have occurred in the last few years prompting an update. Interesting recent publications will be highlighted against a background of established knowledge. In the field of anesthesia, particularly in pediatrics, some contributions have been made concerning intramuscular versus intravenous induction. The need for anticholinergic adjuvants has also been clarified. Neuroapoptosis has been observed in animals and its implications for human subjects are discussed in a general context of neurotoxicity. The most important developments, however, are in the treatment of pain. Neurological and urological side effects strongly question long-term use. Other potentially beneficial effects have also been reported, such as anti-inflammatory and antidepressive effects. There are also indications that ketamine may attenuate postoperative delirium in coronary by-pass patients. More questions have arisen than have been answered. Some have very grave implications. The issue of neuroapoptosis must be clarified. The long-term effects must be further investigated. On the bright side the effects on postoperative delirium, as well as the anti-inflammatory and antidepressive effects, might open new vistas for an old drug.
For ketamine&... more For ketamine's fiftieth birthday, a narrative review of this unique drug in pain management is presented. Its history is traced from its conception, and its heritage, as a phencyclidine offspring, delineated. The earliest roots of the conceptions concerning the mechanisms of action are sought, and then followed in preclinical as well as clinical research. The major proposed mechanisms in the literature are commented on and evaluated. The growth of the clinical evidence for perioperative pain, acute pain, and chronic pain is followed from early attempts to systematic reviews. Finally, an attempt is made to foresee what the next 50 years might hold in store for our 50 years old.
Ketamine in sub-dissociative doses has been shown to have analgesic effects in various pain condi... more Ketamine in sub-dissociative doses has been shown to have analgesic effects in various pain conditions, including neuropathic and phantom-limb pain, where conventional treatment has often failed. Chronic ischemic pain due to lower extremity arteriosclerosis obliterans often responds poorly to analgesics, and the pain-generating mechanisms are not well understood. Eight patients with rest pain in the lower extremity due to arteriosclerosis obliterans were given sub-dissociative doses of 0.15, 0.30, or 0.45 mg/kg racemic ketamine and morphine 10 mg as a 5-min infusion on four separate days in a cross-over, double-blind, randomised protocol. Plasma levels of (S)- and (R)-ketamine and their nor-metabolites were analysed with an enantioselective high-performance liquid chromatography (HPLC) method. Pain levels were evaluated with a visual analogue scale (VAS). Individual pain levels were highly variable during and after all the infusions but the pooled pain levels showed a dose-dependent analgesic effect of ketamine with a transient but complete pain relief in all the patients at the highest dose (0.45 mg/kg). Side-effects, mainly disturbed cognition and perception, were pronounced and dose-dependent. Morphine 10 mg had an analgesic peak at 20 min and 5/8 patients had complete pain relief. These 3 patients also had high baseline pain scores, indicating a higher analgesic potency for the 0.30 and 0.45 mg/kg ketamine doses than for morphine 10 mg. We have demonstrated a potent dose-dependent analgesic effect of racemic ketamine in clinical ischemic pain. Due to a narrow therapeutic window, this analgesic effect is probably best utilised in combination with other analgesics.
Uploads
Papers by Jan Persson