Pamela Pierce Palmer

Age-dependent Opioid Escalation in Chronic Pain Patients

Rapid opioid dose escalation, possibly caused by tolerance, has been observed in some patients on daily opioid therapy, although clinically identifiable characteristics of these patients are unknown. In this retrospective chart review of 206 patients, we examined whether the age of the patient was related to opioid escalation. Initial starting doses of long-acting opioids were similar in younger patients (≤50 yr; 49 ± 3 mg/d oral morphine-equivalent dose) versus older patients (≥60 yr; 42 ± 3 mg/d). Younger patients reached a maximum dose of 452 ± 63 mg/d over 15.0 ± 1.3 mo, whereas older patients achieved a maximum dose of 211 ± 23 mg/d over 14.4 ± 1.5 mo (P < 0.0001). At the last clinic visit, younger-patient dosing averaged 365 ± 61 mg/d, with older patients averaging 168 ± 18 mg/d (P < 0.0001). Only older patients demonstrated a reduction in visual analog scale scores from start of opioid therapy until discharge from the clinic (6.9 ± 0.3 to 5.6 ± 0.3; P < 0.01). These clinical data suggest that age is an important variable in opioid dose escalation. Although factors other than opioid tolerance can result in dose escalation, it is possible that older patients may have a reduced rate of tolerance development.

Presence of opioid receptor-like (ORL1) receptor mRNA splice variants in peripheral sensory and sympathetic neuronal ganglia.

The expression of ORL1 receptor mRNA splice variants is determined in peripheral sensory and sympathetic ganglia and compared to mRNA expression for the three classic opioid receptor subtypes (mu, delta, and kappa) using the method of reverse transcription-polymerase chain reaction. ORL1, mu, delta and kappa receptor subtype mRNAs are present in human dorsal root ganglia (DRG) and trigeminal ganglia and rat DRG. ORL1, mu and delta receptor subtype mRNAs are present in rat superior cervical ganglia and only ORL1 and delta receptor mRNAs are present in rat lumbar sympathetic ganglia. Both the ORL1 mRNA splice variants are present in sensory and sympathetic ganglia, however, expression of the shorter ORL1 receptor mRNA dominates over expression of the longer splice variant in rat brain and DRG, whereas, expression of the longer splice variant is dominant in sympathetic ganglia.

Detection of mRNAs and alternatively spliced transcripts of dopamine receptors in rat peripheral sensory and sympathetic ganglia

The presence of mRNAs for dopamine receptor subtypes and dopamine transporter in rat peripheral sensory and sympathetic ganglia was investigated using polymerase chain reaction (PCR) and DNA sequencing. Dopamine D1, D2, D3, D5 receptor subtype mRNAs and dopamine transporter mRNA were detected in both superior cervical sympathetic ganglia (SCG) and dorsal root ganglia (DRG) in the rat; the expression of D4 mRNA was only detected in DRG. While two alternatively spliced isoforms of D2 were detected in both ganglia, the alternative splicing transcripts for D3 and D4 were only found in the DRG. These results are useful in further studying the roles of dopamine and the effects of dopaminergic agents in the peripheral nervous system.

RGS proteins: new players in the field of opioid signaling and tolerance mechanisms.

In this article we review recent advances in our understanding of the crucial role of the Regulator of G protein Signaling (RGS) proteins in opioid signaling mechanisms and opioid tolerance development. Opioids exert their physiologic effects via complex G protein-coupled receptor-signaling mechanisms, and RGS proteins are now known to tightly regulate the G protein signaling cycle. RGS proteins contain GTPase-accelerating protein activity within their characteristic RGS domain and various other receptor signaling-related properties of their other functional domains. There have been more than 20 RGS proteins reported in the literature, and multiple RGS proteins have been shown to negatively regulate G protein-mediated opioid signaling, facilitate opioid receptor desensitization and internalization, and affect the rate at which opioid tolerance develops. Using RGS proteins as targets for future drug therapy aimed at modulating opioid effectiveness in both acute and chronic pain settings may be an important advance in the treatment of pain.

Age-dependent morphine tolerance development in the rat.

In all age groups, the use of opioids to treat chronic pain conditions has increased, yet the impact of age on opioid tolerance development has not been comprehensively addressed. In this study, we investigated age-related differences in morphine tolerance development in rats. Rats aged 3 wk, 3 mo, 6 mo, and 1 yr were used in the study. Morphine (8 mg/kg) was injected subcutaneously twice each day and its analgesic effect assessed by the change in tail-flick latency using a thermal stimulus 5 min before and 30 min after dosing. Tolerance was defined as a 75% reduction in morphine-induced analgesia compared to Day 1. Rats aged 3 wk, 3 mo, 6 mo, and 1 yr developed tolerance on the 4th, 10th, 14th, and 22nd days of morphine treatment, respectively. Plasma levels of morphine and its metabolites showed that pharmacokinetic differences among the groups did not correlate with the differences in tolerance development. This study demonstrates that morphine tolerance occurs more rapidly in younger rats than older rats and is unlikely to be the result of differences in drug metabolism or clearance. Aging may impact molecular processes involved in tolerance development and provide insight into novel therapeutic targets to delay opioid tolerance development.

Current and developing methods of patient-controlled analgesia.

Moderate-to-severe acute postoperative pain is commonly controlled with opioids administered via programmable intravenous (IV) patient-controlled analgesia (PCA) infusion pumps. Intravenously administered opioids provide effective relief of postoperative pain, and IV PCA enables patients to control their level of analgesia, which has advantages over nurse-administered approaches, including more satisfied patients and improved pain relief. Unfortunately, commonly used opioid analgesics can cause significant adverse effects. Furthermore, IV PCA has drawbacks, such as device programming errors, system errors, medication errors, limitations in patient mobility, and potential for IV tubing kinks, clogging, and transmission of infection. The IV route of administration is also characterized by a rapid, high peak in analgesic drug concentration followed by rapidly decreasing concentrations. Consequently, respiratory depression, excessive sedation, and inadequate pain control can occur. Furthermore, the technical assembly of an infusion pump is often complex and time-consuming. PCA modalities that incorporate superior opioid analgesics, such as sufentanil, and novel noninvasive routes of administration offer great promise for enhancing the patient and caregiver experience with the use of postoperative PCA.

An alternatively spliced transcript of the rat nociceptin receptor ORL1 gene encodes a truncated receptor

Opioid receptor-like protein ORL1, the receptor for the neuropeptide nociceptin (also named orphanin FQ), has two alternatively spliced isoforms in the rat. This alternative splicing event is generated by retaining of intron 3, 81 bases in length, in the mRNA region encoding the second extracellular loop of ORL1. A full-length rat ORL1 receptor has 367 amino acid residues. However, as revealed by sequencing of rat ORL1 genomic DNA and cDNA, the insertion of the unspliced intron 3 brings in an in-frame stop codon and, therefore, creates a truncated open-reading frame encoding only the N-terminal half of ORL1 (from the N-terminus to an alternate extracellular tail C-terminal to the fourth transmembrane domain). The two alternatively spliced transcripts are differentially expressed in tissues. In transfected mammalian cells, the full-length ORL1 displays high-affinity and selective binding for nociceptin, and inhibits the production of cyclic AMP. In contrast, the truncated ORL1 binds nociceptin and other opioid peptides very poorly and non-selectively (affinity in micromolar range), and it does not mediate any inhibitory effects on cyclic AMP production. Apparently, this truncated ORL1 does not function as a receptor for nociceptin or other ligands tested. Such alternative splicing to create a truncated ORL1 receptor might be an endogenous mechanism to negatively regulate nociceptin/ORL1 functions.

Sufentanil Sublingual Tablet System for the Management of Postoperative Pain after Knee or Hip Arthroplasty: A Randomized, Placebo-controlled Study.

Background:Complications with IV patient-controlled analgesia include programming errors, invasive access, and impairment of mobility. This study evaluated an investigational sufentanil sublingual tablet system (SSTS) for the management of pain after knee or hip arthroplasty. Methods:This prospective, randomized, parallel-arm, double-blind study randomized postoperative patients at 34 U.S. sites to receive SSTS 15 &mgr;g (n = 315) or an identical placebo system (n = 104) and pain scores were recorded for up to 72 h. Adult patients with American Society of Anesthesiologists status 1 to 3 after primary total unilateral knee or hip replacement under general anesthesia or with spinal anesthesia that did not include intrathecal opioids were eligible. Patients were excluded if they were opioid tolerant. The primary endpoint was the time-weighted summed pain intensity difference to baseline over 48 h. Secondary endpoints included total pain relief, patient and healthcare professional global assessments, and patient and nurse ease-of-care questionnaires. Results:Summed pain intensity difference (standard error) was higher (better) in the SSTS group compared with placebo (76 [7] vs. −11 [11], difference 88 [95% CI, 66 to 109]; P < 0.001). In the SSTS group, more patients and nurses responded “good” or “excellent” on the global assessments compared with placebo (P < 0.001). Patient and nurse ease-of-care ratings for the system were high in both groups. There was a higher incidence of nausea and pruritus in the SSTS group. Conclusion:SSTS could be an effective patient-controlled pain management modality in patients after major orthopedic surgery and is easy to use by both patients and healthcare professionals.

Involvement of endogenous opioid systems in nociceptin-induced spinal antinociception in rats

The present study investigates the involvement of opioid receptors in the antinociceptive effects of nociceptin in the spinal cord of the rat. Intrathecal administrations of 5 and 10 nmol of nociceptin significantly increase the withdraw response latencies to noxious thermal and mechanical stimulations. This nociceptin-induced antinociceptive effect is significantly attenuated by intrathecal injection of (Nphe(1))nociceptin(1-13)-NH(2), a selective antagonist of the nociceptin receptor (opioid receptor-like receptor ORL1), indicating an ORL1 receptor-mediated mechanism. This antinociceptive effect is also significantly attenuated by intrathecal injections of naloxone (a nonselective opioid receptor antagonist), naltrindole (a selective delta-opioid receptor antagonist), and beta-funaltrexamine (a selective mu-opioid receptor antagonist) in a dose-dependent manner, but not by the selective kappa-opioid receptor antagonist norbinaltorphimine. Since it is unlikely that nociceptin acts by direct binding to opioid receptors, these results suggest a possible interaction between the nociceptin/ORL1 and opioid systems in the dorsal horn of the rat spinal cord.

Novel delivery systems for postoperative analgesia

Moderate-to-severe postoperative pain is usually controlled using a multimodal approach, including opioids. Intravenously administered patient-controlled analgesia (IV PCA) with opioids, popular for over 40 years, enables patients to control their level of analgesia and has advantages over a nurse-administered approach, including more satisfied patients and improved pain relief. Unfortunately, IV PCA has drawbacks such as device programming errors, medication prescribing errors, pump malfunction, limitations on patient mobility, IV patency issues, and transmission of infection. Furthermore, the setup of an infusion pump is often complex, time-consuming, and requires witnessed confirmation. Complicating IV PCA is the problem of commonly used compounds, morphine and hydromorphone, having significantly reduced brain/effector-site permeability and active metabolites, both of which create the risk of delayed adverse events. Novel patient-controlled modalities that incorporate rapid effector site-permeating opioids and non-invasive routes of administration offer great promise to enhance both patient and caregiver experiences with postoperative analgesia systems.