Marieke Niesters

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 Fifty unique studies (including three unpublished studies) were included in the analyses.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.

Ketamine for chronic pain: risks and benefits

The anaesthetic ketamine is used to treat various chronic pain syndromes, especially those that have a neuropathic component. Low dose ketamine produces strong analgesia in neuropathic pain states, presumably by inhibition of the N‐methyl‐D‐aspartate receptor although other mechanisms are possibly involved, including enhancement of descending inhibition and anti‐inflammatory effects at central sites. Current data on short term infusions indicate that ketamine produces potent analgesia during administration only, while three studies on the effect of prolonged infusion (4–14 days) show long‐term analgesic effects up to 3 months following infusion. The side effects of ketamine noted in clinical studies include psychedelic symptoms (hallucinations, memory defects, panic attacks), nausea/vomiting, somnolence, cardiovascular stimulation and, in a minority of patients, hepatoxicity. The recreational use of ketamine is increasing and comes with a variety of additional risks ranging from bladder and renal complications to persistent psychotypical behaviour and memory defects. Blind extrapolation of these risks to clinical patients is difficult because of the variable, high and recurrent exposure to the drug in ketamine abusers and the high frequency of abuse of other illicit substances in this population. In clinical settings, ketamine is well tolerated, especially when benzodiazepines are used to tame the psychotropic side effects. Irrespective, close monitoring of patients receiving ketamine is mandatory, particularly aimed at CNS, haemodynamic, renal and hepatic symptoms as well as abuse. Further research is required to assess whether the benefits outweigh the risks and costs. Until definite proof is obtained ketamine administration should be restricted to patients with therapy‐resistant severe neuropathic pain.

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.

Safety and Efficacy of ARA 290 in Sarcoidosis Patients with Symptoms of Small Fiber Neuropathy: A Randomized, Double-Blind Pilot Study

ARA 290 (a peptide designed to activate the innate repair receptor that arrests injury and initiates cytoprotection, antiinflammation and healing) reduces allodynia in preclinical neuropathy models. We studied the safety and efficacy of ARA 290 to reduce symptoms of small fiber neuropathy (SFN) in patients with sarcoidosis. A total of 22 patients diagnosed with sarcoidosis and symptoms of SFN were enrolled in a double-blind, placebo-controlled exploratory trial consisting of three times weekly intravenous dosing of ARA 290 (2 mg; n = 12) or placebo (n = 10) for 4 wks. Inclusion criteria were a diagnosis of neuropathy and a spontaneous pain score of ≥5 (Brief Pain Inventory [BPI]). Endpoints assessed were changes in pain intensity and the small fiber neuropathy screening list (SFNSL) score, quality of life (SF-36), depressive symptoms (Inventory of Depressive Symptomatology [IDS]) and fatigue (Fatigue Assessment Scale [FAS]). No safety concerns were raised by clinical or laboratory assessments. The ARA 290 group showed significant (p < 0.05) improvement at wk 4 in SFNSL score compared with placebo (Δ −11.5 ± 3.04 versus Δ −2.9 ± 3.34 [standard error of the mean]). Additionally, the ARA 290 group showed a significant change from baseline in the pain and physical functioning dimensions of the SF-36 (Δ −23.4 ± 5.5 and Δ −14.6 ± 3.9, respectively). The mean BPI and FAS scores improved significantly but equivalently in both patient groups. No change was observed in the IDS. ARA 290 appears to be safe in patients with sarcoidosis and can reduce neuropathic symptoms.

Offset analgesia in neuropathic pain patients and effect of treatment with morphine and ketamine.

Background: Offset analgesia, in which a disproportionally large amount of analgesia becomes apparent upon a slight decrease in noxious heat stimulation, has not been described previously in patients with chronic pain. Methods: Offset analgesia responses in 10 patients with neuropathic pain (in both legs) were compared with 10 matched healthy controls and volunteers from a convenience sample (n = 110) with an age range of 6–80 yr. Offset analgesia was defined by the reduction in electronic pain score upon the 1°C decrease in noxious heat stimulus relative to the peak pain score where pain was administered at the volar side of the arm. Results: Offset analgesia was present in healthy volunteers irrespective of age and sex (pain score decrease = 97 ± 1% [mean ± SEM]). In contrast, a reduced or absent offset analgesia response was observed in patients with neuropathic pain (pain score decrease = 56 ± 9% vs. controls 98 ± 1%, P < 0.001). Intravenous treatment with ketamine, morphine, and placebo had no effect on offset analgesia in patients, despite sharp reductions in spontaneous pain scores. Conclusions: These data indicate that offset analgesia is fully developed at the age of 6 yr and does not undergo additional maturation. The reduced or absent responses observed in patients with chronic neuropathic pain indicate the inability to modulate changes in pain stimulation, with perseverance of pain perception in situations in which healthy subjects display signs of strong analgesia. Both central and peripheral sites may be involved in the altered offset analgesia responses in these patients.