Spinal cord stimulation for refractory angina in patients implanted with cardioverter defibrillators: five case reports.

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.

Specific effect of levetiracetam in experimental human pain models.

BACKGROUND: Levetiracetam is a new antiepileptic drug. There is only limited experience with levetiracetam in clinical neuropathic pain. AIM: To test the analgesic effect of levetiracetam in a human experimental pain model in order to obtain preclinical evidence for its potential effect in neuropathic pain. METHODS: Sixteen healthy volunteers completed a randomized, double-blind, cross-over trial with a single oral dose of 1500 mg levetiracetam against placebo. Pain tests included pain detection and tolerance to single electrical stimulation and temporal pain summation threshold to repetitive electrical stimulation (3 Hz) of the sural nerve. RESULTS: Levetiracetam significantly increased the pain tolerance thresholds (p=0.04), and the pain detection thresholds tended to be increased (p=0.06), whereas levetiracetam had no effect on temporal pain summation thresholds (p=0.30). CONCLUSION: Levetiracetam has an analgesic effect in the electrical sural nerve stimulation pain model, but it did not increase temporal pain summation threshold. Levetiracetam may still be effective in clinical neuropathic pain.

The analgesic effect of tramadol after intravenous injection in healthy volunteers in relation to CYP2D6.

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.

Opioid prescriptions before and after high-energy trauma.

OBJECTIVE: To describe the legal use of opioids in adult patients before and after high-energy trauma. DESIGN: The study was a retrospective database study. SETTING: Clinical care outside hospitals. PATIENTS: All patients who suffered high-energy trauma and were brought to Odense University Hospital (OUH), Denmark, in 2007 and 2008 were retrieved from the trauma database. These patients were linked with data on opioid use from the regional prescription database. In all, 938 patients were included. MAIN OUTCOME MEASURE: Redemption of opioid prescription during the 6 months prior to a multitrauma or redemption of two or more prescriptions for opioids 6 months or later after a multitrauma. RESULTS: Of the 938 patients brought to OUH with severe trauma within the study period, 61 patients died (7 percent) and six of these had redeemed prescriptions for opioids within 6 months prior to the trauma (10 percent) compared to 65 patients of the 877 survivors (7 percent) (odds ratio 1.4, nonsignificant). In all, 62 patients (7 percent) redeemed opioid prescriptions later than 6 months after their trauma and in a multivariable analysis, severe injury itself and severe injuries of the lower extremities were associated with redemption of opioid prescription after the trauma. CONCLUSIONS: The authors did not find any correlation between death by trauma and redemption of opioid prescriptions within the 6 months before the trauma. More severe traumas and especially severe traumas to the lower extremities were associated with redemption of opioid prescriptions after multitrauma.

Spinal cord stimulation in patients with painful diabetic neuropathy: a multicentre randomized clinical trial.

Painful diabetic neuropathy (PDN) is a peripheral neuropathic pain condition that is often difficult to relieve. Spinal cord stimulation (SCS) is a proven effective therapy for various types of mixed neuropathic conditions, yet effectiveness of SCS treatment for PDN is not well established. To our knowledge, ours is the first multicentre randomized controlled trial investigating the effectiveness of SCS in patients with PDN. Sixty patients with PDN in the lower extremities refractory to conventional medical therapy were enrolled and followed for 6 months. They were randomized 2:1 to best conventional medical practice with (SCS group) or without (control group) additional SCS therapy, and both groups were assessed at regular intervals. At each follow-up visit, the EuroQoL 5D, the short form McGill Pain Questionnaire (SF-MPQ) and a visual analogue scale (VAS, ranging 0-100) to measure pain intensity were recorded. The average VAS score for pain intensity was 73 in the SCS group and 67 in the control group at baseline. After 6 months of treatment, the average VAS score was significantly reduced to 31 in the SCS group (P<.001) and remained 67 (P=.97) in the control group. The SF-MPQ and EuroQoL 5D questionnaires also showed that patients in the SCS group, unlike those in the control group, experienced reduced pain and improved health and quality of life after 6 months of treatment. In patients with refractory painful diabetic neuropathy, spinal cord stimulation therapy significantly reduced pain and improved quality of life.

Lack of association of OPRM1 and ABCB1 single-nucleotide polymorphisms to oxycodone response in postoperative pain.

PURPOSE: The aim of the study was to search for an association between the single-nucleotide polymorphisms A118G in OPRM1 and C3435T and G2677T/A in ABCB1 and the analgesic effect of intravenous oxycodone in postoperative pain. METHODS: There were 268 patients with postoperative pain after, primarily, thyroidectomy. At given times during the first 24 hours postoperatively, their pain was rated at rest and during activity according to a numeric rating scale (0 = no pain, 10 = worst possible pain) and calculated as pain time area under the curve0-24 hours . A negative answer in a final questionnaire and/or the use of rescue medication categorized a patient as a nonresponder. RESULTS: For OPRM1, there was no difference found between the wild type and the variant allele in the percentages of nonresponders (118AA = 16.4% vs 118AG/118GG = 17.0%, P = 1.0) or in the pain ratings. For ABCB1, no difference was found between the wild type and the variant alleles for single-nucleotide polymorphism tested as percentages of nonresponders (3435CC = 17.5% vs 3435CT/3435TT = 15.8%, P = .85; 2677GG = 17.8% vs 2677GT/2677TT = 15.8%, P = .74) or pain ratings. CONCLUSION: No association was found between the tested single-nucleotide polymorphisms in OPRM1 and ABCB1 and changes in the analgesic effect of oxycodone.

The antinociceptive effect and adverse drug reactions of oxycodone in human experimental pain in relation to genetic variations in the OPRM1 and ABCB1 genes.

The aim of this study was to search for a possible association between the variant allele of the single nucleotide polymorphisms A118G in the OPRM1 gene and C3435T and G2677T/A in the ABCB1 gene and altered antinociceptive effect and adverse drug reactions of oxycodone. Thirty-three healthy subjects exposed to experimental pain including electrical stimulation and the cold pressor test were included. A118G: We found that the variant G allele was associated with reduced antinociceptive effect as measured by pain tolerance thresholds to single electrical nerve stimulation (8% increase vs. 25% for the wild-type carriers, P = 0.007). C3435T: The carriers of the variant T allele generally had less adverse drug reactions on oxycodone than the carriers of the wild-type genotype. G2677T/A: The carriers of the variant T allele had a better antinociceptive effect of oxycodone than the carriers of the wild-type genotype in the cold pressor test (25% reduction vs. 15%, P = 0.015 in the discomfort rating and 25% reduction vs. 12%, P = 0.007 in the pain time AUC) and less adverse drug reactions. The combined wild-type genotype 3435CC-2677GG was associated with less antinociceptive effect of oxycodone in the discomfort rating of the cold pressor test (13% reduction vs. 23%, P = 0.019) and more severe adverse drug reactions than the carriers of the variant alleles. We found a moderate association between less antinociceptive effect of oxycodone and the variant allele of A118G. There was strong association between less adverse drug reactions of oxycodone and the variant alleles of C3435T and G2677T/A.

The effects of gabapentin in human experimental pain models.

Background The antidepressant drugs imipramine and venlafaxine relieve clinical neuropathic pain and have been shown to increase pain thresholds in healthy volunteers during repetitive electrical sural nerve stimulation causing temporal pain summation, whereas pain during the cold pressor test is unaltered by these drugs. If this pattern of effect in experimental pain models reflects potential efficacy in clinical neuropathic pain, the pain summation model may potentially be used to identify new drugs for such pain conditions. Gabapentinoids are evidence-based treatments of clinical neuropathic pain and could contribute with additional knowledge of the usefulness of the pain summation model. The aim of this study To test the analgesic effect of the gabapentinoid gabapentin in a sural nerve stimulation pain model including temporal pain summation and the cold pressor test. Method 18 healthy volunteers completed a randomized, double-blind, cross-over trial with medication of 600 mg gabapentin orally dosed 3 times over 24 h against placebo. Pain tests were performed before and 24 h after medication including pain detection and tolerance to single sural nerve stimulation and pain summation threshold to repetitive stimulation (3 Hz). Peak pain intensity and discomfort were rated during a cold pressor test. Results Compared to placebo, gabapentin had a highly significant effect on the threshold of pain summation to repetitive electrical sural nerve stimulation (P = 0.009). Gabapentin significantly increased the pain tolerance threshold to single electrical sural nerve stimulation (P = 0.04), whereas the pain detection threshold to single electrical sural nerve stimulation tended to be increased (P = 0.06). No significant differences were found on pain ratings during the cold pressor test. Conclusion Gabapentin had a selective hypoalgesic effect in a human experimental pain model of temporal pain summation and the results lend further support to the usefulness of the pain summation model to identify drugs for neuropathic pain.

The hypoalgesic effect of oxycodone in human experimental pain models in relation to the CYP2D6 oxidation polymorphism.

Oxycodone is O-demethylated by CYP2D6 to oxymorphone which is a potent micro-receptor agonist. The CYP2D6 oxidation polymorphism divides the Caucasian population in two phenotypes: approximately 8% with no enzyme activity, poor metabolizers (PM) and the remainder with preserved CYP2D6 activity, extensive metabolizers (EM). The objective of the study was to determine if the analgesic effect of oxycodone in human experimental pain depends on its metabolism to oxymorphone. The analgesic effect of oxycodone was evaluated in a randomized, placebo-controlled, double-blinded, crossover experiment including 33 (16 EM and 17 PM) healthy volunteers. Pain tests were performed before and 1, 2, 3 and 4 hr after medication and included pain detection and tolerance thresholds to single electrical sural nerve stimulation, pain summation threshold to repetitive electrical sural nerve stimulation and the cold pressor test with rating of discomfort and pain-time area under curve (AUC(0-2 min.)). For single sural nerve stimulation, there was a less pronounced increase in thresholds on oxycodone in pain detection (9% vs. 20%, P = 0.02, a difference of 11%, CI: 2%-20%) and pain tolerance thresholds (15% vs. 26%, P = 0.037, a difference of 10%, CI: 1%-20%) for PM compared with EM. In the cold pressor test, there was less reduction in pain AUC on oxycodone for PM compared with EM (14% vs. 26%, P = 0.012, a difference of 12%, CI: 3%-22%). The plasma oxymorphone/oxycodone ratio was significantly lower in PM compared with EM (P < 0.001). Oxycodone analgesia seems to depend both on oxycodone itself and its metabolite oxymorphone.

Spinal cord stimulation has proven benefit on pain and quality of life in patients with angina pectoris when less invasive therapies have failed.

Background. Since 1988, spinal cord stimulation (SCS) has been used at Odense University Hospital for patients with refractory angina pectoris. The aim of our prospective study was to evaluate the long-term effects of SCS on pain, activities of daily living (ADLs), quality of life (QOL), sleep hygiene, and physical functioning for patients with angina pectoris. Methods. Before and after placement of SCS for patients with intractable angina pectoris, we performed structured telephone interviews questioning for pain relief, ADLs (Nottingham Health Profile), physical functioning (Seattle Angina Questionnaire) and sleep hygiene. Results. Out of 150 patients with SCS over 15 years, 41 patients had died, 46 patients had their devices explanted, and four patients did not participate or could not be reached. Three patients had less than 6 months of follow-up and were therefore not included in our analysis. The beneficial effects of SCS treatment for intractable angina pectoris were reduction in pain and improvement in QOL. Sleep pattern and physical functioning were not improved to the same extent as reduction in pain or improvement in QOL. Almost all of our SCS-treated patients did recommend SCS for intractable angina pectoris. About 30% of patients discontinued treatment, the most common cause being electrode displacement and malfunction of the system. Other reasons for discontinued therapy were the evolvement of invasive treatment options such as coronary artery bypass graft and PTCA and use of such options in some patients during our prolonged observation period. Conclusion. This survey shows that SCS leads to a 70-80% improvement in pain, which, in turn, leads to improvement in QOL, whereas, physical condition and sleep pattern did not improve to the same extent.