Background: Oxycodone is a semi‐synthetic opioid with a μ‐receptor agonist‐mediated effect in several pain conditions, including post‐operative pain. Oxycodone is metabolized to its active metabolite ...oxymorphone by O‐demethylation via the polymorphic CYP2D6. The aim of this study was to investigate whether CYP2D6 poor metabolizers (PMs) yield the same analgesia post‐operatively from intravenous oxycodone as extensive metabolizers (EMs).
Methods: Two hundred and seventy patients undergoing primarily thyroid surgery or hysterectomy were included and followed for 24 h post‐operatively. The CYP2D6 genotype was blinded until study procedures had been completed for all patients. All patients received intravenous oxycodone as pain treatment for 24 h post‐operatively and morphine 5 mg was used as escape medication. A responder was characterized as a patient without the need for escape medication and a positive evaluation in a questionnaire 24 h post‐operatively.
Results: Twenty‐four patients were PM (8.9%) and 246 were EM (91.1%). One PM (4.17%, CI=0.1–21.1) was a non‐responder and 42 EM (17.07%, CI=12.6–22.4) were non‐responders. The non‐responder rate did not differ between the two genotypes (P=0.14). There was no difference in the total consumption of oxycodone between the two genotypes (EM=14.7 mg, CI=13.0–16.4 and PM=13.0 mg, CI=8.9–17.0, P=0.42). The mean oxymorphone/oxycodone ratios were 0.0031 and 0.00081 in the EMs and PMs, respectively (P<0.0001).
Conclusion: This study showed for the first time in patients that the oxymorphone formation depends on CYP2D6, but we found no difference in the post‐operative analgesic effect of intravenous oxycodone between the two CYP2D6 genotypes.
Objective
Tramadol hydrochloride (INN, tramadol) exerts its antinociceptive action through a monoaminergic effect mediated by the parent compound and an opioid effect mediated mainly by the ...O‐demethylated metabolite (+)‐M1. O‐demethylation is catalyzed by cytochrome P450 (CYP) 2D6. Paroxetine is a very potent inhibitor of CYP2D6. The objective of this study was to investigate the influence of paroxetine pretreatment on the biotransformation and the hypoalgesic effect of tramadol.
Methods
With and without paroxetine pretreatment (20 mg daily for 3 consecutive days), the formation of M1 and the analgesic effect of 150 mg of tramadol were studied in 16 healthy extensive metabolizers of sparteine in a randomized, double‐blind, placebo‐controlled, 4‐way crossover study by use of experimental pain models.
Results
With paroxetine pretreatment, the area under the plasma concentration‐time curve (AUC) of (+)‐ and (−)‐tramadol was increased (37% P = .001 and 32% P = .002, respectively), and the corresponding AUCs of (+)‐ and (−)‐M1 were decreased (67% P = .0004 and 40% P = .0008, respectively). (+)‐M1 and (−)‐M1 could be determined in all subjects throughout the study period regardless of paroxetine pretreatment. The sums of differences between postmedication and premedication values of pain measures differed between the placebo/tramadol and the placebo/placebo combination, with median values as follows: pressure pain tolerance threshold, 390 kPa (95% confidence interval CI, 211 to 637 kPa) versus −84 kPa (95% CI, − 492 to −32 kPa) (P = .001); single sural nerve stimulation pain tolerance threshold, 25.8 mA (95% CI, 15.3 to 29.8 mA) versus 9.0 mA (95% CI, 1.5 to 14.8 mA) (P = .005); pain summation threshold, 10.7 mA (95% CI, 5.2 to 17.6 mA) versus 5.0 mA (95% CI, 2.8 to 11.2 mA) (P = .066); cold pressor pain, −4.2 cm · s (95% CI, −6.8 to −1.9 cm · s) versus −0.4 cm · s (− 1.4 to 1.4 cm · s) (P = .002); and discomfort, −4.7 cm (95% CI, −10.6 to −2.8 cm) versus 0.5 cm (−0.1 to 1.4 cm) (P = .002). The sums of differences of the paroxetine/tramadol combination also differed from placebo/tramadol for some of the measures, with median values as follows: cold pressor pain, −2.2 cm · s (95% CI, −3.7 to −0.4 cm · s) (P = .036, compared with placebo/tramadol); and discomfort, −2.0 cm (95% CI, −5.6 to −1.2 cm) (P = .056). For the other measures, the hypoalgesic effect was retained on the paroxetine/tramadol combination, with median values as follows: pressure pain tolerance threshold, 389 kPa (95% CI, 141 to 715 kPa) (P = .278, compared with placebo/tramadol); single sural nerve stimulation pain tolerance threshold, 12.5 mA (95% CI, 6.2 to 28.3 mA) (P = .278); and pain summation threshold, 8.2 mA (95% CI, 4.4 to 14.6 mA) (P = .179). Paroxetine in combination with placebo showed no analgesic effect.
Conclusions
It is concluded that paroxetine at a dosage of 20 mg once daily for 3 consecutive days significantly inhibits the metabolism of tramadol to its active metabolite M1 and reduces but does not abolish the hypoalgesic effect of tramadol in human experimental pain models, particularly in opioid‐sensitive tests.
Clinical Pharmacology & Therapeutics (2005) 77, 312–323; doi: 10.1016/j.clpt.2004.11.002
Tramadol analgesia results from a monoaminergic effect by tramadol itself and an opioid effect of its metabolite (+)-M1 formed by O-demethylation of tramadol by CYP2D6. In this study we sought to ...determine the impact of (+)-M1 on the analgesic effect of tramadol evaluated by experimental pain models. The effect of an IV injection of 100 mg tramadol on experimental pain was studied 15-90 min after dosing in volunteers, 10 extensive metabolizers with CYP2D6 and 10 poor metabolizers without CYP2D6 in 2 placebo-controlled trials. The pain tests included detection and tolerance threshold to single electrical sural nerve stimulation, pain summation threshold to repetitive electrical sural nerve stimulation (temporal summation), and the cold pressor test. In extensive metabolizers, tramadol reduced discomfort experienced during the cold pressor test (P = 0.002). In poor metabolizers, the pain tolerance thresholds to sural nerve stimulation were increased (P = 0.04). (+)-M1 could be detected in the serum samples from all extensive metabolizers except one, but (+)-M1 was below the limit of determination in all poor metabolizers. The opioid effect of (+)-M1 appears to contribute to the analgesic effect of tramadol, but the monoaminergic effect of tramadol itself seems to create an analgesic effect.
Background
Tricyclic antidepressants relieve neuropathic pain, and the analgesic properties of tricyclic antidepressants are substantiated in human experimental pain models. It has been speculated ...that drugs with a selective inhibition of presynaptic reuptake of both serotonin and noradrenaline could have an analgesic effect comparable to the analgesic effect of tricyclic antidepressants.
Objective
Our objective was to evaluate the analgesic effect of the serotonin‐noradrenaline reuptake inhibitor venlafaxine in human experimental pain models.
Method
The study was carried out as a randomized, placebo‐controlled, double‐blind, crossover experiment that included 16 healthy volunteers. A 37.5‐mg dose of venlafaxine was given orally 4 times with 12‐hour intervals, and pain tests were performed before and 3 hours after the second and fourth doses. Pain tests included the determination of pain detection and tolerance thresholds to pressure, pain detection and tolerance thresholds on single electrical transcutaneous stimulation of the sural nerve, pain temporal summation on repetitive electrical sural nerve stimulation, and pain experienced during the cold pressor test.
Results
Venlafaxine increased thresholds for pain tolerance after single electrical stimulation (P = .005) and pain summation (P = .01) on repetitive stimulation but did not alter the thresholds for pain detection after single electrical sural nerve stimulation. Venlafaxine did not alter pain experienced during the cold pressor test or increase the pressure pain thresholds.
Conclusion
Venlafaxine increases the pain tolerance threshold to electrical sural nerve stimulation and the threshold at which pain increases (pain summation). The impact of venlafaxine on pain summation in this experimental pain model on repetitive stimulation may indicate a potential analgesic effect for clinical neuropathic pain.
Clinical Pharmacology & Therapeutics (2001) 69, 245–251; doi: 10.1067/mcp.2001.114873
PainData is an electronic internet-based clinical pain registry established to improve the understanding and treatment of high-impact chronic pain. The primary aim of this paper is to describe ...socio-demographics, pain characteristics, quality of life, and treatment values at baseline and follow-up in individuals referred to public and private interdisciplinary pain centers in Denmark between 2018 and 2020.
Self-reported patient-reported outcomes collected through PainData before (n=12,257) and after (n=4,111) treatment across 13 public and private interdisciplinary specialized pain centers in Denmark (87% of all pain centers in Denmark) are described.
Mean duration of pain was 10 years, and one in three patients reported chronic widespread pain. More than 40% reported opioid use, and 50% had tried four or more different treatment modalities prior to referral. More than 60% reported poor sleep, severe fatigue, and memory and/or concentration deficits. Mean scores on pain catastrophizing, fear of movement, and pain-related disability were high, whereas scores on pain acceptance and self-efficacy were low. Physical and mental health were rated as poor and fair, respectively. One in four patients reported being very much improved or much improved after treatment. Items commonly reported after treatment were increased knowledge about pain, emotions and mood (66.5%), being better at accepting life with chronic pain (63.1%), and improved activity pacing (60.6%).
The PainData registry, containing data from a large cohort of individuals, can help to improve the understanding and treatment of high-impact chronic pain, and collaborations with other researchers are welcome.
The hypoalgesic effect of single oral doses of 100 mg imipramine and 125 mg codeine was evaluated in a randomised, placebo-controlled, double-blind, 3-way cross-over experiment including 18 healthy ...volunteers. Pain tests were performed before and 90, 180, 270, 360 and 450 min after medication. The tests included determination of pain tolerance thresholds to pressure, pain detection/tolerance thresholds to single electrical sural nerve stimulation and pain summation at tolerance threshold to repetitive electrical sural nerve stimulation (temporal summation) and pain experienced during the cold pressor test, rated as peak pain intensity, pain average intensity and discomfort. Compared to placebo, imipramine significantly increased pressure pain tolerance threshold (P = 0.03) and increased pain tolerance threshold (P = 0.05) and pain summation threshold (P = 0.03), but not pain detection threshold to electrical stimulation. Imipramine did not cause significant changes in pain perception during the cold pressor test. Codeine significantly increased pressure pain tolerance threshold (P = 0.02), pain detection (P = 0.04) and pain tolerance threshold (P = 0.01) and pain summation threshold (P = 0.02) to electrical stimulation. In addition, codeine reduced the pain experienced during the cold pressor test (P = 0.04-0.003). It is concluded that both imipramine and codeine inhibit temporal pain summation, whereas only codeine reduces cold pressor pain. Pain summation may be a key mechanism in neuropathic pain. Imipramine has a documented effect on such pain conditions on temporal summation. The present study showed that codeine also inhibits temporal summation, which is in line with the clinical observations indicating that opioids relieve neuropathic pain.
Background: The aim of the present study was to investigate whether a combination of rofecoxib and gabapentin could improve pain relief and reduce opioid requirements, compared with rofecoxib alone, ...during the first 5 days after tonsillectomy.
Methods: In a randomized, double‐blind, placebo‐controlled study, 49 patients received gabapentin 1200 mg pre‐operatively, followed by gabapentin 2 × 600 mg on the day of operation and gabapentin 3 × 600 mg for the next 5 days, or placebo. Both groups were given rofecoxib 50 mg daily. In the post‐operative care unit, intravenous morphine was administered in doses of 2.5 mg on request. From 4 h to 5 days post‐operatively, ketobemidone was offered as escape drug. Pain at rest and during swallowing, and side‐effects, were assessed using a four‐point verbal rating scale.
Results: As a result of the global withdrawal of rofecoxib, the study had to be terminated prematurely. This report comprises the results from 22 patients in the gabapentin group and 27 patients in the placebo group. Gabapentin reduced ketobemidone requirements during the first 24 h post‐operatively 4.5 mg (standard deviation, 3.0 mg) in the placebo group vs. 2.0 mg (standard deviation, 2.0 mg) in the gabapentin group; P < 0.003. Gabapentin induced more dizziness (P < 0.002), gait disturbance (P < 0.02) and vomiting (P < 0.05) during days 0–5 than placebo. No other statistically significant differences were observed.
Conclusion: Gabapentin reduced opioid requirements in the first 24 h after tonsillectomy. The benefits of the reduced opioid intake may be overshadowed by the drawbacks of side‐effects.
Patients implanted with a cardioverter defibrillator (ICD) who are suffering from refractory angina pectoris could benefit from spinal cord stimulation (SCS) due to the well-documented pain relieving ...effect. However, the combined treatment remains controversial. The aim of the study is to report successful long-term treatment with SCS in five patients implanted with cardioverter defibrillators. The combined treatments with ICD and thoracic epidural electrical stimulation were used in five patients with refractory angina pectoris. During the procedure of the implantation, testing with the maximal tolerable level of stimulation was carried out to exclude inference with the ICD. The following treatment with SCS has in all cases been successful, with significant pain relief and improved quality of life. There were no incidences of inappropriate defibrillator shocks. Spinal cord stimulation for refractory angina pectoris can be performed in patients implanted with cardioverter defibrillators without interference. However, individual testing during implantation or re-programming the devices is mandatory in order to assess optimal safety in each patient.
Objective
Our objective was to examine the interaction between fluvoxamine and tolbutamide to confirm that fluvoxamine inhibits CYP2C9.
Methods
The study was carried out as an open, randomized, ...crossover design with 14 healthy participants. In period A, all volunteers took 500 mg of tolbutamide orally. In period B, the volunteers were randomly assigned to one of two groups. Each group took either 150 mg or 75 mg of fluvoxamine a day for 5 days (day −3 to day 2). The groups then took 500 mg of tolbutamide as a single dose (day 0). In both periods, blood and urine were sampled at regular intervals. Plasma was analyzed for tolbutamide, and urine was analyzed for tolbutamide and its two metabolites, 4‐hydroxytolbutamide and carboxytolbutamide by means of HPLC.
Results
During treatment with fluvoxamine, there was a statistically significant decrease in the median of the total clearance of tolbutamide, from 845 mL/h to 688 mL/h, among the volunteers who received 75 mg/d. There was a reduction that reached borderline statistical significance in the group that received 150 mg/d of tolbutamide. The clearance by means of 4‐hydroxytolbutamide and carboxytolbutamide was significantly reduced in both groups (ie, from 901 mL/h to 318 mL/h in the group that received 150 mg of tolbutamide per day and from 723 mL/h to 457 mL/h in the group that received 75 mg of tolbutamide per day). Thus there was a tendency toward a more pronounced inhibition of the 4‐hydroxylation during treatment with 150 mg/d of fluvoxamine compared with 75 mg/d, but the difference was not statistically significant.
Conclusion
Fluvoxamine is a moderate inhibitor of CYP2C9 in vivo.
Clinical Pharmacology & Therapeutics (2001) 69, 41–47; doi: 10.1067/mcp.2001.112689
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