Chronic Morphine Modulates PDGFR-ß and PDGF-B Expression and Distribution in Dorsal Root Ganglia and Spinal Cord in Male Rats.

The analgesic effect of opioids decreases over time due to the development of analgesic tolerance. We have shown that inhibition of the platelet-derived growth factor beta (PDGFR-ß) signaling eliminates morphine analgesic tolerance in rats. Although the PDGFR-ß and its ligand, the platelet-derived growth factor type B (PDGF-B), are expressed in the substantia gelatinosa of the spinal cord (SG) and in the dorsal root ganglia (DRG), their precise distribution within different cell types of these structures is unknown. Additionally, the impact of a tolerance-mediating chronic morphine treatment, on the expression and distribution of PDGF-B and PDGFR-ß has not yet been studied. Using immunohistochemistry (IHC), we found that in the spinal cord, PDGFR-ß and PDGF-B were expressed in neurons and oligodendrocytes and co-localized with the mu-opioid receptor (MOPr) in opioid naïve rats. PDGF-B was also found in microglia and astrocytes. Both PDGFR-ß and PDGF-B were detected in DRG neurons but not in spinal primary afferent terminals. Chronic morphine exposure did not change the cellular distribution of PDGFR-ß or PDGF-B. However, PDGFR-ß expression was downregulated in the SG and upregulated in the DRG. Consistent with our previous finding that morphine caused tolerance by inducing PDGF-B release, PDGF-B was upregulated in the spinal cord. We also found that chronic morphine exposure caused a spinal proliferation of oligodendrocytes. The changes in PDGFR-ß and PDGF-B expression induced by chronic morphine treatment suggest potential mechanistic substrates underlying opioid tolerance.

KATP Channel Prodrugs Reduce Inflammatory and Neuropathic Hypersensitivity, Morphine-Induced Hypersensitivity, and Precipitated Withdrawal in Mice.

Previous studies show ATP-sensitive potassium (KATP) channel openers can reduce hypersensitivity associated with chronic pain models in rodents, and reduce morphine tolerance. Many agonists of KATP channels are not soluble in physiologically relevant vehicles, requiring adaptation for clinical use. This study compared the antinociceptive activity of novel KATP channel targeting prodrugs, CKLP1, CKLP2, and CF3-CKLP. These prodrugs are activated by endogenous alkaline phosphatase enzymes present in the peripheral and central nervous systems. Analgesic capabilities of intrathecally injected prodrugs were tested in rodent models of spinal nerve ligation (SNL) and complete Freund's adjuvant (CFA) as models for neuropathic and inflammatory pain, respectively. CKLP1 and CKLP2 significantly increased mechanical paw withdrawal thresholds 1-2 hours after intrathecal administration in the SNL model, but all three prodrugs were able to attenuate hypersensitivity up to 7 days after CFA treatment. The reduction of opioid tolerance and opioid-induced hypersensitivity in mice treated chronically with morphine was significantly reduced in CKLP1 and CKLP2 treated animals. Prodrug cleavage was confirmed in mouse spinal cords using liquid chromatography. These studies may aid in the further development of KATP channel prodrugs for use in treatments of chronic pain, opioid tolerance, and withdrawal. SIGNIFICANCE STATEMENT: The cromakalim prodrugs, CKLP1, CKLP2, and CF3-CKLP1 reduced hypersensitivity in inflammatory and neuropathic pain models in male and female mice. CKLP1 and CKLP2 also reduced morphine-induced hypersensitivity in a mouse model of chronic morphine exposure. CKLP2 reduced jumping and rearing behaviors after naloxone-induced precipitated morphine withdrawal. Taken together, CKLP2 demonstrates the potential for development as a non-opioid analgesic drug.

The EGFR-STYK1-FGF1 axis sustains functional drug tolerance to EGFR inhibitors in EGFR-mutant non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) patients harboring activating mutations in epidermal growth factor receptor (EGFR) are sensitive to therapy with EGFR tyrosine kinase inhibitors (TKI). Despite remarkable clinical responses using EGFR TKI, surviving drug tolerant cells serve as a reservoir from which drug resistant tumors may emerge. This study addresses the need for improved efficacy of EGFR TKI by identifying targets involved in functional drug tolerance against them. To this aim, a high-throughput siRNA kinome screen was performed using two EGFR TKI-sensitive EGFR-mutant NSCLC cell lines in the presence/absence of the second-generation EGFR TKI afatinib. From the screen, Serine/Threonine/Tyrosine Kinase 1 (STYK1) was identified as a target that when downregulated potentiates the effects of EGFR inhibition in vitro. We found that chemical inhibition of EGFR combined with the siRNA-mediated knockdown of STYK1 led to a significant decrease in cancer cell viability and anchorage-independent cell growth. Further, we show that STYK1 selectively interacts with mutant EGFR and that the interaction is disrupted upon EGFR inhibition. Finally, we identified fibroblast growth factor 1 (FGF1) as a downstream effector of STYK1 in NSCLC cells. Accordingly, downregulation of STYK1 counteracted the afatinib-induced upregulation of FGF1. Altogether, we unveil STYK1 as a valuable target to repress the pool of surviving drug tolerant cells arising upon EGFR inhibition. Co-targeting of EGFR and STYK1 could lead to a better overall outcome for NSCLC patients.

Cell-Intrinsic Mechanisms of Drug Tolerance to Systemic Therapies in Cancer.

In patients with cancer with metastatic disease, the rate of complete tumor response to systemic therapies is low, and residual lesions persist in the majority of patients due to early molecular adaptation in cancer cells. A growing body of evidence suggests that a subpopulation of drug-tolerant persister cells-a reversible phenotype characterized by reduced drug sensitivity and decreased cell proliferation-maintains residual disease and may serve as a reservoir for resistant phenotypes. The survival of these residual tumor cells can be caused by reactivation of specific signaling pathways, phenotypic plasticity (i.e., transdifferentiation), epigenetic or metabolic reprogramming, downregulation of apoptosis as well as transcriptional remodeling. In this review, we discuss the molecular mechanisms that enable adaptive survival in drug-tolerant cells. We describe the main characteristics and dynamic nature of this persistent state, and highlight the current therapeutic strategies that may be used to interfere with the establishment of drug-tolerant cells, as an alternative to improve objective response to systemic therapies and delay the emergence of resistance to improve long-term survival.

Activation of the spinal EGFR signaling pathway in a rat model of cancer-induced bone pain with morphine tolerance.

Cancer-induced bone pain (CIBP) is considered to be one of the most difficult pain conditions to treat. Morphine, an analgesic drug, is widely used in clinical practice, and long-term use of morphine can lead to drug tolerance. Recent reports have suggested that inhibitors of epidermal growth factor receptor (EGFR) may have analgesic effects in cancer patients suffering from pain. Therefore, we sought to determine whether EGFR signaling was involved in morphine tolerance (MT) in a rat model of cancer-induced bone pain. In this study, Walker 256 mammary gland carcinoma cells were inoculated into the tibias of rats to provoke cancer-induced bone pain. Then, morphine was intrathecally administered twice daily for seven consecutive days to induce drug tolerance. We observed sustained increased in the protein levels of EGFR, p-EGFR, ERK1/2, and p-ERK1/2 during the development of morphine tolerance in rats with cancer-induced bone pain by western blotting. The EGFR level was significantly increased in the MT and CIBP + MT groups, and EGFR was colocalized with markers of microglia and neurons in the spinal cords of rats. Inhibition of EGFR by a small molecule inhibitor markedly attenuated the degree of morphine tolerance and decreased the number of microglia, and the protein levels of EGFR, p-EGFR, ERK1/2, and p-ERK1/2 were also reduced. In summary, our results suggest that the activation of the EGFR signaling pathway in spinal microglia plays an important modulatory role in the development of morphine tolerance and that inhibition of EGFR may provide a new therapeutic option for cancer-induced bone pain.

Relationship between level of response to alcohol and acute tolerance.

BACKGROUND: A low level of response (low LR) to alcohol correlates with the later development of alcohol-related problems. Although some of the underpinnings of LR are understood, little is known about the potential relationship between LR and acute tolerance. The current analyses tested the hypothesis that a low LR will be explained in part by more intense acute tolerance to alcohol during a drinking session. METHODS: Data were generated through a reanalysis of data from 120 individuals who were 18- to 25-year-old, sex-matched pairs of low and high LR drinkers who at baseline did not meet criteria for an alcohol use disorder. Each subject participated in an oral alcohol challenge in which they consumed about 0.7 ml ethanol per kg and acute tolerance was measured as the differences in alcohol's effects at similar breath alcohol levels (BrACs) during the rising and falling breath alcohol concentration (BrAC) curve. Measures included aspects of the Subjective High Assessment Scale (SHAS) and body sway. RESULTS: Contrary to our hypothesis, but similar to results with other alcohol measures, acute tolerance was significantly attenuated in low LR compared with high LR individuals on most SHAS scores. Neither LR group demonstrated acute tolerance to alcohol for sleepiness or body sway. Men and women did not differ on any of these measures. CONCLUSION: These data do not support a role of acute tolerance in the low LR to alcohol as measured by subjective feelings of intoxication or body sway in these subjects, findings that were similar across males and females. In addition, consistent with the literature, the analyses demonstrated differences across measures such that acute tolerance was observed for most measures of subjective effects but not for body sway. Among the subjective effects, acute tolerance was observed for alcohol's intoxicating effect but not for feeling sleepy.

NADPH-Oxidase 2 Promotes Autophagy in Spinal Neurons During the Development of Morphine Tolerance.

Repeated morphine administration results in analgesic tolerance. However, the underlying mechanism of morphine analgesic tolerance remains unclear. NADPH-oxidase 2 (NOX2) is the first discovered NADPH oxidase, which mainly functions to produce reactive oxygen species. Its specific role in morphine tolerance has not been fully investigated. In this work, we found that chronic morphine administration significantly increased the expression of NOX2 in spinal cord. Pretreatment of NOX2 inhibitor blocked the upregulation of NOX2 and autophagy markers, including LC3B and P62, and consequently the development of morphine tolerance. NOX2 and LC3B were both colocalized with NeuN in spinal dorsal horn in morphine-tolerant rats. Our results suggest that the increased autophagy activity in spinal neurons promoted by NOX2 activation contributes to the development of morphine tolerance. NOX2 may be considered as a new therapeutic target for morphine tolerance.

Tolerability of Molecular-targeted Agents for Hepatocellular Carcinoma Treatment in Haemophiliacs.

BACKGROUND: Hepatocellular carcinoma (HCC) is considered a leading cause of death in patients with haemophilia. Recent advances in the treatment of unresectable HCC with molecular-targeted agents (MTAs) have led to better clinical outcomes. However, the tolerability of MTAs by haemophilic patients with HCC remains unclear. AIM: This study aimed to compare the tolerability of MTAs in such patients. PATIENTS AND METHODS: From January 2011 to October 2020, five haemophilic patients with HCC were treated with MTAs. Adverse events were assessed in comparison with 265 non-haemophilic patients with HCC. RESULTS: The prevalence of hand-foot skin reaction was not higher in the haemophiliacs than in the non-haemophiliacs, whereas the rate of haemorrhagic events was higher in the haemophiliacs (6.0% versus 40.0%, p=0.037). CONCLUSION: Haemophiliacs tolerate long-term MTA use, without the occurrence of life-threatening complications. However, careful observation and prevention are needed for MTA-related gastrointestinal bleeding in haemophiliacs.

Inhibition of the phosphoinositide 3-kinase-AKT-cyclic GMP-c-Jun N-terminal kinase signaling pathway attenuates the development of morphine tolerance in a mouse model of neuropathic pain.

Research presented here sought to determine if opioid induced tolerance is linked to activity changes within the PI3Kγ-AKT-cGMP-JNK intracellular signaling pathway in spinal cord or peripheral nervous systems. Morphine or saline injections were given subcutaneously twice a day for five days (15 mg/kg) to male C57Bl/6 mice. A separate cohort of mice received spinal nerve ligation (SNL) one week prior to the start of morphine tolerance. Afterwards, spinal cord, dorsal root ganglia, and sciatic nerves were isolated for quantifying total and phosphorylated- JNK levels, cGMP, and gene expression analysis of Pik3cg, Akt1, Pten, and nNos1. This pathway was downregulated in the spinal cord with increased expression in the sciatic nerve of morphine tolerant and morphine tolerant mice after SNL. We also observed a significant increase in phosphorylated- JNK levels in the sciatic nerve of morphine tolerant mice with SNL. Pharmacological inhibition of PI3K or JNK, using thalidomide, quercetin, or SP600125, attenuated the development of morphine tolerance in mice with SNL as measured by thermal paw withdrawal. Overall, the PI3K/AKT intracellular signaling pathway is a potential target for reducing the development of morphine tolerance in the peripheral nervous system. Continued research into this pathway will contribute to the development of new analgesic drug therapies.

Hydrogen enriched saline alleviates morphine tolerance via inhibiting neuroinflammation, GLT-1, GS nitration and NMDA receptor trafficking and functioning in the spinal cord of rats.

The development and maintenance of morphine tolerance showed association with neuroinflammation and dysfunction of central glutamatergic system (such as nitration of glutamate transporter). Recent evidence indicated that hydrogen could reduce the levels of neuroinflammation and oxidative stress, but its role in morphine tolerance has not been studied. The rats were intrathecally administered with morphine (10 µg/10 µL each time, twice/day for 5 days). Hydrogen enriched saline (HS) or saline was given intraperitoneally at 1, 3 and 10 mL/kg for 10 min before each dose of morphine administration. The tail-flick latency, mechanical threshold and thermal latency were assessed one day (baseline) before and daily for up to 5 days during morphine injection. The pro-inflammatory cytokine expressions [tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß), IL-6)] (by western blotting), astrocyte activation (by immunofluorescence and western blotting), and nitration of glutamate transporter-1 (GLT-1) and glutamine synthetase (GS) (by immunoprecipitation), membrane and total expression of N-methyl-d-aspartic acid (NMDA) receptor NR1 and NR2B subunits were carried out in the spinal dorsal horns. Chronic morphine administration induced antinociceptive tolerance, and together led to increased TNF-α, IL-1ß and IL-6 expression, astrocyte activation, GLT-1 and GS nitration, increased membrane and total NR1, NR2B expression. Injection of HS attenuated morphine tolerance in a dose-dependent manner, decreased proinflammatory cytokine expression, inhibited astrocyte activation, decreased GLT-1 and GS nitration, and inhibited membrane trafficking of NMDA receptor. Our result showed that hydrogen pretreatment prevented morphine tolerance by reducing neuroinflammation, GLT-1, GS nitration, NMDA receptor trafficking in the spinal dorsal horn. Pretreatment with hydrogen might be considered as a novel therapeutic strategy for the prevention of morphine tolerance.

Single-cell transcriptional changes associated with drug tolerance and response to combination therapies in cancer.

Tyrosine kinase inhibitors were found to be clinically effective for treatment of patients with certain subsets of cancers carrying somatic mutations in receptor tyrosine kinases. However, the duration of clinical response is often limited, and patients ultimately develop drug resistance. Here, we use single-cell RNA sequencing to demonstrate the existence of multiple cancer cell subpopulations within cell lines, xenograft tumors and patient tumors. These subpopulations exhibit epigenetic changes and differential therapeutic sensitivity. Recurrently overrepresented ontologies in genes that are differentially expressed between drug tolerant cell populations and drug sensitive cells include epithelial-to-mesenchymal transition, epithelium development, vesicle mediated transport, drug metabolism and cholesterol homeostasis. We show analysis of identified markers using the LINCS database to predict and functionally validate small molecules that target selected drug tolerant cell populations. In combination with EGFR inhibitors, crizotinib inhibits the emergence of a defined subset of EGFR inhibitor-tolerant clones. In this study, we describe the spectrum of changes associated with drug tolerance and inhibition of specific tolerant cell subpopulations with combination agents.

Donepezil attenuates the development of morphine tolerance in rats with cancer-induced bone pain: The role of cortical N-methyl-D-aspartate receptors.

Cancer-induced bone pain (CIBP), which is associated with poor quality of life, is most commonly treated using opioids. However, long-term use of morphine for analgesia induces tolerance and can diminish the treatment's effectiveness. The mechanisms that underlie morphine tolerance have been reported to be related to the inflammation of the nervous system and hyperactivation of N-methyl-D-aspartate receptors (NMDARs). Donepezil is an anti-inflammatory and neuroprotective drug that is thought to alleviate morphine tolerance. In this study, we aimed to investigate the effect of three different dosages of donepezil (1, 1.5 and 2 mg/kg) on morphine tolerance in rats with CIBP, and the possible involvement of donepezil-mediated NMDAR subunit 1 (NR1). We found that donepezil can prolong the analgesic efficacy of morphine and delay the development of chronic morphine tolerance. Furthermore, continuous morphine injection increased the expression of NR1, and this was suppressed by co-administration with donepezil using both western blotting and immunofluorescence. Our findings demonstrate that donepezil has the potential to attenuate morphine tolerance, possibly by inhibiting NR1 activity in the cortex.

Cannabidiol-enriched oil in children and adults with treatment-resistant epilepsy-does tolerance exist?

AIM: To evaluate the long-term effectiveness of cannabidiol (CBD)-enriched oil for the treatment of refractory epilepsy and to assess the development of tolerance to its anti-seizure effect. METHODS: A prospective study of 92 consecutive patients (age 1-37 years, mean-11.8 years) with treatment resistant epilepsy who were treated with cannabis oil extract (CBD/tetrahydrocannabinol [THC] ratio of 20:1). Mean monthly seizure frequency was reported by the patients/their parents during monthly clinic visits. Tolerance was defined as either the need to increase the dose by ≥30% due to reduced treatment efficacy or as an increase of ≥30% in mean monthly seizure frequency in patients treated for at least 3 months with no change in other anti-seizure medications. RESULTS: Mean follow-up time was 19.8 ± 12.5 months (range 3-45). Mean CBD dose was 11.3 (4-38) mg/kg/day. Twenty-nine (31%) patients discontinued treatment due to lack of effect or adverse reactions, which were reported in 51% (47/87) of the patients. Overall responder rate (>50% seizures reduction) was 54%, whereas 8 patients (9%) became seizure-free. Eighty-four patients were included in the tolerance analysis. Tolerance was observed in 21 (25%) patients after a mean duration of 7.3 ± 5.4 months of CBD-enriched oil treatment. There was a negative correlation between epilepsy duration and tolerance development (p = 0.038). CONCLUSIONS: We report for the first time the plausible appearance of tolerance to cannabidiol-enriched oil. This may limit treatment efficacy in the long-term clinical management of refractory epilepsy in both pediatric and adult population. Further studies are needed to investigate potential mechanisms.

Long induction of tolerance to imatinib.

Imatinib is used to treat several haematological and solid malignancies. Cutaneous side effects could often limit the use of this medication. We present a case of a 62-year-old woman with a history of a gastrointestinal stromal tumour that developed a delayed cutaneous adverse reaction 10 days after starting imatinib 400 mg daily. She developed the same symptoms with reintroduction at a dose of 100 mg and with an alternative tyrosine kinase inhibitor, nilotinib 50 mg/day. Given that imatinib was considered her best treatment, she underwent a long induction of drug tolerance (IDT) protocol to imatinib. Patient tolerated the medication without further reactions for 6 months and had improvement of her cancer per last imaging studies. IDT should be considered in delayed hypersensitivity reactions to imatinib after a failed reintroduction of the drug or when no other equally effective agents are available.

Risk Factors for Prolonged Opioid Use and Effects of Opioid Tolerance on Clinical Outcomes After Anterior Cervical Discectomy and Fusion Surgery.

STUDY DESIGN: Retrospective study. OBJECTIVE: The aim of this study was to determine risk factors for prolonged opioid use and to investigate whether opioid-tolerance affects patient-reported outcomes following anterior cervical discectomy and fusion (ACDF) surgery. SUMMARY OF BACKGROUND DATA: There is a lack of consensus on risk factors that can affect continued opioid use after cervical spine surgery and the influence of opioid use on patient-reported outcomes. METHODS: Ninety-two patients who underwent ACDF for degenerative cervical pathologies were retrospectively identified and their opioid usage before surgery was investigated using a state-sponsored prescription drug monitoring registry. Opioid-naïve and opioid tolerant groups were defined using criteria most consistent with the Federal Drug Administration (FDA) definition. Patient-reported outcomes were then collected, including the Short Form-12 (SF-12) Physical Component (PCS-12) and Mental Component (MCS-12), the Neck Disability Index (NDI), the Visual Analogue Scale Neck (VAS neck) and the Visual Analogue Scale Arm (VAS Arm) pain scores. Logistic regression was used to determine predictors for prolonged opioid use following ACDF. Univariate and multivariate analyses were conducted to compare change in outcomes over time between the two groups. RESULTS: Logistic regression analysis demonstrated that opioid tolerance was a significant predictor for prolonged opioid use after ACDF (odds ratio [OR]: 18.2 [1.46, 226.4], P = 0.02). Duration of usage was also found to be a significant predictor for continued opioid use after surgery (OR: 1.10 [1.0, 1.03], P = 0.03). No other risk factors were found to be significant predictors. Both groups overall experienced improvements in patient-reported outcomes after surgery. Multiple linear regression analysis, controlling for patient demographics, demonstrated that opioid-tolerant user status positively affected change in outcomes over time for NDI (ß = -13.7 [-21.8,-5.55], P = 0.002) and PCS-12 (ß = 6.99 [2.59, 11.4], P = 0.003) but no other outcomes measured. CONCLUSION: Opioid tolerance was found to be a significant predictor for prolonged opioid use after ACDF. Additionally, opioid-naïve and opioid-tolerant users experienced overall improvements across PROMs following ACDF. Opioid-tolerance was associated with NDI and PCS-12 improvements over time compared to opioid-naïve users. LEVEL OF EVIDENCE: 4.

Effect of Essential Oil of Zhumeria majdae on Morphine Tolerance and Dependence in Mice.

OBJECTIVE: To evaluate the effects of Zhumeria majdae essential oil (ZMEO) on morphine dependence and tolerance in mice. METHODS: ZMEO (10, 20, and 40 mg/kg) and clonidine (0.1 mg/kg) as the positive control were injected intraperitoneally (i.p.). The effect of ZMEO and clonidine on the dependence were evaluated by counting the number of jumps induced by naloxone (5 mg/kg) while the tolerance was evaluated by the tail-flick test. RESULTS: ZMEO at the dose of 10 mg/kg during the development period led to a significant inhibition of morphine tolerance (P<0.01), while it led to reduced morphine dependence with the doses of 20 and 40 mg/kg. ZMEO at two dose levels of 20 and 40 mg/kg indicated significant antinociceptive activity (P>0.01), and significantly reduced the withdrawal signs (number of jumps) of mice (P>0.01). CONCLUSIONS: ZMEO had significant effects on morphine tolerance and dependence. The linalool rich essential oil of Z. majdae plays a major role in the reduction of tolerance and dependence induced by morphine.

Longitudinal Toxicity over Time (ToxT) analysis to evaluate tolerability: a case study of lenalidomide in the CALGB 50401 (Alliance) trial.

Evaluation of tolerability is increasingly relevant for patients with haematological malignancies treated with chronically administered therapies. Adverse events from these agents might affect the ability of patients to tolerate treatment over time. Conventional toxicity tables that include the incidence of high-grade adverse events, defined by the Common Terminology Criteria for Adverse Events, do not provide information on the time profile of these adverse events or reflect the continuous, lower grade symptomatic toxicities that are particularly relevant to treatment tolerability for patients living with indolent disease. Modern approaches to the evaluation and reporting of toxicity that capture the tolerability of treatment to the patient are imperative. In this Viewpoint, we present a focused, pilot, and longitudinal Toxicity over Time analysis of adverse events from lenalidomide and lenalidomide with rituximab in patients with follicular lymphoma treated in the CALGB 50401 (Alliance; NCT00238238) trial to define the trajectory of adverse events and quantify the burden of continuous, low-grade events. Toxicity over Time analyses provided clinically relevant descriptions of neutropenia and fatigue trajectories caused by lenalidomide that were not identified by standard analysis of the maximum grade events defined by the Common Terminology Criteria for Adverse Events. Systematic, rigorous incorporation of patient-reported outcomes in clinical trials will be crucial to our understanding of the tolerability of chronically administered therapies in patients with haematological malignancies.

Recommendations for Managing Opioid-Tolerant Surgical Patients within Enhanced Recovery Pathways.

PURPOSE OF REVIEW: One of the consequences of the opioid epidemic is an increase in the number of opioid-tolerant patients. These patients are at higher risk for readmission and longer hospital stays following surgery. Enhanced recovery after surgery (ERAS) pathways can be used as a framework for providing high-quality comprehensive care to patient population. It is estimated that as many as 15% of all surgery patients in the USA are receiving opioids going into surgery. The number of patients on medication maintenance therapy with long-acting opioids such as methadone or partial mu receptor agonists like buprenorphine is rising, which poses a challenge for perioperative healthcare providers. RECENT FINDINGS: Preoperative opioid tolerance is an independent predictor for increased length of hospital stays, high costs, and increased readmission rates following surgery. Given the recent trends, it is likely that more opioid-tolerant patients will require surgery in near future. Enhanced recovery programs can be used to provide a framework for high-quality care to opioid-tolerant patients throughout all phases of the perioperative process. To improve the quality of care of opioid-tolerant patients, we present five general recommendations for clinicians to consider and possibly incorporate into ERAS programs and care protocols. Recommendations include the following: opioid-tolerant patients should not be excluded from ERAS programs; opioid-tolerant patients should be identified preoperatively; programs should establish standard practices for patients on medication maintenance therapy and buprenorphine; opioid-tolerant patients should receive multimodal analgesia perioperatively; and opioid-tolerant patients should receive coordinated follow up after surgery.

Opioid analgesia: recent developments.

PURPOSE OF REVIEW: Opioids are potent drugs for the treatment of severe pain, but they are burdened by detrimental side-effects, such as respiratory depression, addiction, sedation and constipation. Their clinical application is undisputed in acute (e.g. perioperative) and cancer pain, but their use in chronic nonmalignant pain has met increasing scrutiny and has contributed to the opioid crisis. Thus, novel analgesics with reduced side-effects are badly needed. RECENT FINDINGS: Current research topics include enkephalinase inhibitors, allosteric and multivalent ligands, biased opioid receptor signaling and selective activation of peripheral opioid receptors in injured tissues. SUMMARY: Opioids still appear to be most promising among current approaches in the development of analgesics. Basic knowledge about pathophysiology of clinical pain and novel insights in pharmacology suggest that the most interesting perspectives are augmenting endogenous opioid actions and selectively targeting peripheral opioid receptors. The latter approach is additionally supported by evidence from clinical studies. Some biased, multivalent and peripherally selective agonists have advanced to phase III trials, but novel drugs have not become available for clinical application. Future strategies in analgesic drug development might include public-private partnerships and nonprofit pharmaceutical companies, as exemplified by the AIDS crisis and proposals to combat antibiotic resistance.

Antinociceptive and Immune Effects of Delta-9-Tetrahydrocannabinol or Cannabidiol in Male Versus Female Rats with Persistent Inflammatory Pain.

Chronic pain is the most common reason reported for using medical cannabis. The goal of this research was to determine whether the two primary phytocannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), are effective treatments for persistent inflammatory pain. In experiment 1, inflammation was induced by intraplantar injection of Complete Freund's adjuvant (CFA). Then THC (0.0-4.0 mg/kg, i.p.) or CBD (0.0-10 mg/kg, i.p.) was administered twice daily for 3 days. On day 4, THC, CBD, or vehicle was administered, and allodynia, hyperalgesia, weight-bearing, locomotor activity, and hindpaw edema were assessed 0.5-4 hours postinjection. In experiment 2, CFA or mineral oil (no-pain control)-treated rats were given THC (2.0 mg/kg, i.p.), CBD (10 mg/kg, i.p.), or vehicle in the same manner as in experiment 1. Four hours postinjection on day 4, serum samples were taken for analysis of cytokines known to influence inflammatory pain: interleukin (IL)-1ß, IL-6, IL-10, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α THC dose-dependently reduced pain-related behaviors but did not reduce hindpaw edema, and little tolerance developed to THC's effects. In contrast, CBD effects on inflammatory pain were minimal. THC produced little to no change in serum cytokines, whereas CBD decreased IL-1ß, IL-10, and IFN-γ and increased IL-6. Few sex differences in antinociception or immune modulation were observed with either drug, but CFA-induced immune activation was significantly greater in males than females. These results suggest that THC may be more beneficial than CBD for reducing inflammatory pain in that THC maintains its efficacy with short-term treatment in both sexes and does not induce immune activation. SIGNIFICANCE STATEMENT: The pain-relieving effects of cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) are examined in male and female rats with persistent inflammatory pain to determine whether individual phytocannabinoids could be a viable treatment for men and women with chronic inflammatory pain. Additionally, sex differences in the immune response to an adjuvant and to THC and CBD are characterized to provide preliminary insight into immune-related effects of cannabinoid-based therapy for pain.