Leon Aarts

Incidence, Reversal, and Prevention of Opioid-induced Respiratory Depression.

Opioid treatment of pain is generally safe with 0.5% or less events from respiratory depression. However, fatalities are regularly reported. The only treatment currently available to reverse opioid respiratory depression is by naloxone infusion. The efficacy of naloxone depends on its own pharmacological characteristics and on those (including receptor kinetics) of the opioid that needs reversal. Short elimination of naloxone and biophase equilibration half-lives and rapid receptor kinetics complicates reversal of high-affinity opioids. An opioid with high receptor affinity will require greater naloxone concentrations and/or a continuous infusion before reversal sets in compared with an opioid with lower receptor affinity. The clinical approach to severe opioid-induced respiratory depression is to titrate naloxone to effect and continue treatment by continuous infusion until chances for renarcotization have diminished. New approaches to prevent opioid respiratory depression without affecting analgesia have led to the experimental application of serotinine agonists, ampakines, and the antibiotic minocycline.

Do sex differences exist in opioid analgesia? A systematic review and meta-analysis of human experimental and clinical studies

&NA; Although a contribution of sex in opioid efficacy has garnered much attention, the confirmation and direction of any such difference remain elusive. We performed a systematic review of the available literature on sex differences in &mgr; and mixed &mgr;/&kgr; opioid effect on acute and experimental pain. Fifty unique studies (including three unpublished studies) were included in the analyses. Across the 25 clinical studies on &mgr;‐opioids there was no significant sex‐analgesia association. Restricting the analysis to patient‐controlled analgesia (PCA) studies (irrespective of the opioid) yielded greater analgesia in women (n = 15, effect size 0.22, 95% c.i. 0.02–0.42, P = 0.028). Further restricting the analysis to PCA morphine studies yielded an even greater effect in women (n = 11, effect size = 0.36, 95% c.i. 0.17–0.56, P = 0.003). Meta‐regression indicated that the longer the duration of PCA, the difference in effect between the sexes further increased. Across experimental pain studies on &mgr;‐opioids women had greater antinociception from opioids (n = 11, effect size = 0.35; 95% c.i. 0.01–0.69, P = 0.047), which was predominantly due to 6 morphine studies. Female patients had greater &mgr;/&kgr; opioid analgesia (n = 7, effect size 0.84; 95% c.i. 0.25–1.43, P = 0.005), but no sex‐analgesia association was present in experimental studies (n = 7). Sex differences exist in morphine‐induced analgesia in both experimental pain studies and clinical PCA studies, with greater morphine efficacy in women. The data on non‐morphine &mgr; and mixed &mgr;/&kgr;‐opioids are less convincing and require further study.

Off-pump versus on-pump coronary artery bypass grafting: oxidative stress and renal function

OBJECTIVES Oxidative stress and renal dysfunction occur in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass (on-pump CABG). Whether the same adverse effects also occur during off-pump CABG is the question in this study. METHODS Forty patients, 27 men and 13 women, undergoing elective CABG were included; 20 patients underwent on-pump CABG and 20 patients underwent off-pump CABG. Renal and ischemia/reperfusion injury parameters were studied, as well as malondialdehyde as a parameter for oxidative stress. RESULTS The renal function measured as the mean urinary creatinine excretion decreased significantly during surgery for the on-pump CABG group from 7.62+/-4.74 before surgery to 3.07+/-1.49 mmol/l after surgery, whereas no changes occurred in the off-pump CABG group. The mean urinary concentrations of hypoxanthine, xanthine and malondialdehyde expressed as creatinine ratios for the on-pump group increased significantly from 1.92+/-1.36, 6.06+/-3.62 and 0.21+/-0.07 before surgery to 11.88+/-5.77, 13.11+/-6.61 and 0.57+/-0.31 mmol/mol creatinine, respectively at arrival to the intensive care unit (ICU). During the next time-points, the purines and malondialdehyde decreased to 9.21+/-7.46, 7.55+/-3.95 and 0.32+/-0.13 mmol/mol creatinine, respectively after a 20 h stay at the ICU. For the off-pump CABG group, the mean ratios also increased significantly from 1.71+/-1.38, 2.01+/-0.96 and 0.16+/-0.10 before surgery to 4.73+/-3.19, 5.15+/-3.74 and 0.23+/-0.17 mmol/mol creatinine, respectively at arrival to the ICU. During the next time-points, the ratios of xanthine and malondialdehyde decreased to 3.80+/-2.92 and 0.24+/-0.13 mmol/mol creatinine, respectively. The ratio for hypoxanthine reached the highest ratio (6.97+/-5.67 mmol/mol creatinine) after a 9 h stay at the ICU, after which the ratio decreased to 5.98+/-5.56 mmol/mol creatinine after a 20 h stay at the ICU. However, all ratios from the on- and off-pump CABG patients still remained elevated compared with preoperative ratios. In addition, all ratios for the on-pump CABG group were elevated significantly at all time-points for xanthine, at time-points T2 and T4 for hypoxanthine and at time-point T2 for malondialdehyde as compared with the off-pump CABG group. CONCLUSIONS Only mild signs of oxidative stress and no renal dysfunction were found during and after off-pump CABG compared with on-pump CABG.

Opioid-induced respiratory depression in paediatrics: a review of case reports

Opioids remain the cornerstone of modern-day pain treatment, also in the paediatric population. Opioid treatment is potentially life-threatening, although there are no numbers available on the incidence of opioid-induced respiratory depression (OIRD) in paediatrics. To get an indication of specific patterns in the development/causes of OIRD, we searched PubMed (May 2012) for all available case reports on OIRD in paediatrics, including patients 12 yr of age or younger who developed OIRD from an opioid given to them for a medical indication or due to transfer of an opioid from their mother in the perinatal setting, requiring naloxone, tracheal intubation, and/or resuscitation. Twenty-seven cases are described in 24 reports; of which, seven cases were fatal. In eight cases, OIRD was due to an iatrogenic overdose. Three distinct patterns in the remaining data set specifically related to OIRD include: (i) morphine administration in patients with renal impairment, causing accumulation of the active metabolite of morphine; (ii) codeine use in patients with CYP2D6 gene polymorphism associated with the ultra-rapid metabolizer phenotype, causing enhanced production of the morphine; and (iii) opioid use in patients after adenotonsillectomy for recurrent tonsillitis and/or obstructive sleep apnoea, where OIRD may be related to hypoxia-induced enhancement of OIRD. Despite the restrictions of this approach, our analysis does yield an important insight in the development of OIRD, with specific risk factors clearly present in the data.

Tapentadol potentiates descending pain inhibition in chronic pain patients with diabetic polyneuropathy

BACKGROUND Tapentadol is an analgesic agent for treatment of acute and chronic pain that activates the µ-opioid receptor combined with inhibition of neuronal norepinephrine reuptake. Both mechanisms are implicated in activation of descending inhibitory pain pathways. In this study, we investigated the influence of tapentadol on conditioned pain modulation (CPM, an experimental measure of endogenous pain inhibition that gates incoming pain signals as a consequence of a preceding tonic painful stimulus) and offset analgesia (OA, a test in which a disproportionally large amount of analgesia becomes apparent upon a slight decrease in noxious heat stimulation). METHODS Twenty-four patients with diabetic polyneuropathy (DPN) were randomized to receive daily treatment with tapentadol sustained-release (SR) [average daily dose 433 (31) mg] or placebo for 4 weeks. CPM and OA were measured before and on the last day of treatment. RESULTS Before treatment, none of the patients had significant CPM or OA responses. At week 4 of treatment, CPM was significantly activated by tapentadol SR and coincided with significant analgesic responses. CPM increased from 9.1 (5.4)% (baseline) to 14.3 (7.2)% (placebo) and 24.2 (7.7)% (tapentadol SR, P<0.001 vs placebo); relief of DPN pain was also greater in patients treated with tapentadol than placebo (P=0.028). Neither placebo nor tapentadol SR treatment had an effect on the magnitude of the OA responses (P=0.78). CONCLUSIONS Tapentadols analgesic effect in chronic pain patients with DPN is dependent on activation of descending inhibitory pain pathways as observed by CPM responses. CLINICAL TRIAL REGISTRATION The study was registered at trialregister.nl under number NTR2716.

Ketamine for the treatment of chronic non-cancer pain

Importance of the field: Worldwide the number of patients affected by chronic pain is growing and conventional treatment is often insufficient. Recently the importance of the N-methyl-d-aspartate receptor (NMDAR) in the mechanisms and maintenance of chronic pain was established. Ketamine (introduced in the 1960s as an anesthetic) is the most studied NMDAR antagonist in the treatment of various chronic pain syndromes. Areas covered in this review: The pharmacology, safety and toxicology of ketamine are discussed. Further, electronic databases were scanned for prospective, randomized controlled trials that assessed ketamines analgesic effect in patients with chronic pain. The focus of this review is on trials published after 2008 that applied long-term intravenous infusions. What the reader will gain: While most studies on intravenous ketamine show acute analgesic effects, three recent trials on long-term ketamine treatment (days to weeks) demonstrate the effectiveness of ketamine in causing long-term (months) relief of chronic pain. Despite these positive results, further studies are needed on safety/toxicity issues. Other administration modes are less effective in causing long-term pain relief. Take home message: There is now evidence form a limited number of studies that pain relief lasting for months is observed after long-term intravenous ketamine infusion, suggesting a modulatory effect of ketamine in the process of chronic pain, possibly via blockade of upregulated NMDAR.

Effect of ketamine on endogenous pain modulation in healthy volunteers

&NA; Inhibitory and facilitatory descending pathways, originating at higher central nervous system sites, modulate activity of dorsal horn nociceptive neurons, and thereby influence pain perception. Dysfunction of inhibitory pain pathways or a shift in the balance between pain facilitation and pain inhibition has been associated with the development of chronic pain. The N‐methyl‐d‐aspartate receptor antagonist ketamine has a prolonged analgesic effect in chronic pain patients. This effect is due to desensitization of sensitized N‐methyl‐d‐aspartate receptors. Additionally, ketamine may modulate or enhance endogenous inhibitory control of pain perception. Diffuse noxious inhibitory control (DNIC) and offset analgesia (OA) are 2 mechanisms involved in descending inhibition. The present study investigates the effect of a ketamine infusion on subsequent DNIC and OA responses to determine whether ketamine has an influence on descending pain control. Ten healthy subjects (4 men/6 women) received a 1‐hour placebo or S(+)‐ketamine (40 mg per 70 kg) infusion on 2 separate occasions in random order. Upon the termination of the infusion, DNIC and OA responses were obtained. After placebo treatment, significant descending inhibition of pain responses was present for DNIC and OA. In contrast, after ketamine infusion, no DNIC was observed, but rather a significant facilitatory pain response (P < 0.01); the OA response remained unchanged. These findings suggest that the balance between pain inhibition and pain facilitation was shifted by ketamine towards pain facilitation. The absence of an effect of ketamine on OA indicates differences in the mechanisms and neurotransmitter influences between OA and DNIC. Diffuse noxious inhibitory control responses following a 1‐hour low‐dose ketamine treatment displayed facilitation of pain in response to experimental noxious thermal stimulation.

Population pharmacokinetic—pharmacodynamic modeling of ketamine-induced pain relief of chronic pain

Aims: Pharmacological treatment of chronic (neuropathic) pain is often disappointing. In order to enhance our insight in the complex interaction between analgesic drug and chronic pain relief, we performed a pharmacokinetic—pharmacodynamic (PK—PD) modeling study on the effect of S(+)‐ketamine on pain scores in Complex Regional Pain Syndrome type 1 (CRPS‐1) patients.

Drug-induced liver injury following a repeated course of ketamine treatment for chronic pain in CRPS type 1 patients: A report of 3 cases

&NA; Studies on the efficacy of ketamine in the treatment of chronic pain indicate that prolonged or repetitive infusions are required to ensure prolonged pain relief. Few studies address ketamine‐induced toxicity. Here we present data on the occurrence of ketamine‐induced liver injury during repeated administrations of S(+)‐ketamine for treatment of chronic pain in patients with complex regional pain syndrome type 1 as part of a larger study exploring possible time frames for ketamine re‐administration. Six patients were scheduled to receive 2 continuous intravenous 100‐hour S(+)‐ketamine infusions (infusion rate 10–20 mg/h) separated by 16 days. Three of these patients developed hepatotoxicity. Patient A, a 65‐year‐old woman, developed an itching rash and fever during her second exposure. Blood tests revealed elevated liver enzymes (alanine transaminase, alkaline phosphatase, aspartate transaminase, and γ‐glutamyl transferase, all ⩾3 times the upper limit of normal) and modestly increased eosinophilic leukocytes. Patient E, a 48‐year‐old woman, developed elevated liver enzymes of similar pattern as Patient A during her second ketamine administration and a weakly positive response to antinuclear antibodies. In a third patient, Patient F, a 46‐year‐old man, elevated liver enzymes (alanine transaminase and γ‐glutamyl transferase) were detected on the first day of his second exposure. In all patients, the ketamine infusion was promptly terminated and the liver enzymes slowly returned to reference values within 2 months. Our data suggest an increased risk for development of ketamine‐induced liver injury when the infusion is prolonged and/or repeated within a short time frame. Regular measurements of liver function are therefore required during such treatments. During repeated ketamine infusion for treatment of CRPS1, three patients developed liver injury probably allergic in nature.

Mini extracorporeal circuit for coronary artery bypass grafting: initial clinical and biochemical results: a comparison with conventional and off-pump coronary artery bypass grafts concerning global oxidative stress and alveolar function.

Background: The new concept of mini-extracorporeal circulation (MECC) for coronary artery bypass grafts (MCABG) consists of minimal priming volume, a heparin-coated closed circuit, a centrifugal pump, active drainage, blood cardioplegia and a cell-saving device. The potential organ protective effect of this technique during CABG is unknown. Initial clinical outcomes, oxidative stress, alveolar shunting and need for blood transfusion were investigated for MCABG patients. Subsets of these data were compared to outcomes of matched groups of patients operated conventionally (CCABG) and off-pump (OPCAB). Methods: Data of 184 patients were gathered and analysed from a prospective observational database system. This database consists of the initial experience with the first 114 MCABG operations. Of these, the clinical outcome was investigated. In a subset of 60 MCABGs, need for transfusion was monitored and compared to 60 CCABGs. Serum concentrations of malondialdehyde (MDA), allantoin/urate ratios, shunt fractions and lung epithelium-specific proteins (CC16) were measured as biomarkers of damage during MCABG, CCABG and OPCAB (n-30). Results: Patient groups were similar concerning age, risk and number of distal anastomoses. Clinical outcomes are shown for MCABGs only. During MCABG, need for trans-fusion was significantly reduced compared to CCABG (pB/0.001). Serum concentrations of MDA and allantoin/urate ratios showed significantly reduced oxidative stress during MCABG compared to CCABG. During MCABG, F-shunts were reduced shortly after surgery. Increased concentrations of pneumoprotein CC16 were measured during CCABG compared to MCABG (data submitted). Conclusion: Short-term clinical outcomes of MCABG patients are satisfactory. Compared to CCABG the need for transfusion is significantly reduced when a MECC is used. Oxidative stress parameters show a tendency towards improved global organ protection compared to CCABG. F-shunt fractions and CC16 concentrations suggest reduced alveolar damage during MCABG. In a prospective study, the protective effect of mini-CABG has to be confirmed.