Impact of the CYP2D6 genotype on post-operative intravenous oxycodone analgesia.

BACKGROUND: Oxycodone is a semi-synthetic opioid with a mu-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.

Paroxetine, a cytochrome P450 2D6 inhibitor, diminishes the stereoselective O-demethylation and reduces the hypoalgesic effect of tramadol.

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 x s (95% CI, -6.8 to -1.9 cm x s) versus -0.4 cm x s (-1.4 to 1.4 cm x 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 x s (95% CI, -3.7 to -0.4 cm x 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.

Specific effect of venlafaxine on single and repetitive experimental painful stimuli in humans.

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.

Fluvoxamine inhibits the CYP2C9 catalyzed biotransformation of tolbutamide.

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.

The analgesic effect of codeine as compared to imipramine in different human experimental pain models.

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.

[Avulsion fracture of the ischial tuberosity. A rare lesion whose early diagnosis and correct treatment may prevent late sequelae]. / Afrivningsfraktur af tuber ischiadicum. En sjaelden laesion hvor tidlig diagnose og korrekt behandling kan forhindre senfolger.

Avulsion fractures of the ischial tuberosity are often mistaken for sprains or a muscle tears. We present two cases of displaced fractures with a diagnostic delay of eighteen months and two years, respectively. Both cases were treated conservatively and resulted in discomfort on sitting and in one case persistent functional disability. Since early diagnosis is important for a successful treatment, an anteroposterior radiograph of the pelvis is recommended in patients presenting a history and symptoms indicating a lesion in the posterior aspect of the upper thigh. Accumulated experience indicates, that acute displaced fractures should be treated by open reduction and internal fixation.

[Influence of local air suction on the density of air-borne bacteria during cementation of alloplasties]. / Punktsugs indflydelse på koncentrationen af bakteriebaerende partikler i luften under cementering af alloplastikker.

At joint replacement operations local air suction is used to reduce the air pollution from organic solvents in the operation theatre during insertion of cement and prosthesis. In order to find out whether the local suction in an ultraclean-air operation theatre with laminar airflow influenced the number of colony forming units (cfu) of bacterial in vicinity of the wound, one m3 of air was sampled 20 cm and one metre from the wound before, during and after use of local suction during insertion of cement and prosthesis using a Sartorius membrane filter sampler. There was no significant difference between the groups in the numbers of cfu of bacteria found. It is concluded that use of local air suction over the operative area while cementing hip prosthesis does not affect the number of bacteria in the vicinity of the operation.

[Ambulatory knee arthroscopy in arthroscopic surgery under local anesthesia]. / Ambulant knaeartroskopi med artroskopisk kirurgi i lokalanaestesi.

After introducing knee arthroscopy in local anaesthesia as a standard regime in outpatients, we want to describe our experiences from 403 arthroscopies performed in 401 patients, aged 15-80 years, mean 37 years. Diagnostic arthroscopy was performed successfully in 397 of 403 cases. Arthroscopic surgery was indicated in 203 patients and carried out in 188 cases. It was possible to resect 144 of 158 tears of the meniscus. In conclusion, outpatient arthroscopy of the knee with transarthroscopic surgery in local anaesthesia using high dose lidocaine and no sedation is a valuable tool, and should be used on a larger scale. It is possible to carry out diagnostic arthroscopy and arthroscopic surgery in most patients, especially concerning resections of menisci.

The effect of gabapentin on post-operative pain following tonsillectomy in adults.

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 x 600 mg on the day of operation and gabapentin 3 x 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.