Opioid Adjuvant Research Articles

Ketamine subcutaneous continuous infusion for depressive symptoms at home: A case report beyond pain use.

Ketamine has been widely used in refractory pain as an opioid adjuvant. Evidence suggests that ketamine can also have an essential role in easing depressive symptoms. Its rapid onset of action makes it a valuable choice in palliative care. We present a case of a 70-year-old man with stage IV renal carcinoma and bone metastasis. The main symptoms included neuropathic pain, depression, and a persistent and severe desire for death. We started continuous subcutaneous infusion with morphine 30 mg and ketamine 100 mg/day. The dose of ketamine was incremented to the maximum of 250 mg/day. During the 28-day treatment, we observed an overall improvement in neuropathic pain, depressive symptoms, and other end-of-life psychological aspects of distress. Only minor psychological side effects were identified, which were controlled by using midazolam in the continuous subcutaneous infusion. Some studies have already demonstrated the benefits of ketamine use in alleviating depression, using parental infusion or oral formulas, which are administered in hospice care. Our report enhances the benefit of the subcutaneous route for palliative patients cared for at home.

Sustained release local anesthetics for pain management: relevance and formulation approaches.

This review attempted to ascertain the rationale for the formulation of sustained-release local anesthetics and summarize the various formulation approaches designed to date to achieve sustained and localized local analgesic effects. The incidence of pain, which is the concern of patients as well as health care professionals, is increasing due to accidents, surgical procedures, and other diseases. Local anesthetics can be used for the management of moderate to severe acute and chronic pain. They also allow regional analgesia, in situations where the cause and source of the pain are limited to a particular site or region, without the need for loss of consciousness or systemic administration of other analgesics thereby decreasing the risk of potential toxicities. Though they have an interesting antipain efficacy, the short duration of action of local anesthetics makes the need for their multiple injections or opioid adjuvants mandatory. To overcome this problem, different formulations are being designed that help achieve prolonged analgesia with a single dose of administration. Combination with adjuvants, liposomal formulations, lipid-based nanoparticles, thermo-responsive nanogels, microspheres, microcapsules, complexation with multivalent counterions and HP-β-CD, lipid-based nanoparticles, and bio-adhesive films, and polymeric matrices are among the approaches. Further safety studies are required to ensure the safe and effective utilization of sustained-release local anesthetics. Moreover, the release kinetics of the various formulations should be adequately established.

Correlation between Oral Thiamine as an Opioid Adjuvant and Cathecol-O-Methyltransferase Enzyme Levels in Cervical Cancer Patients

BACKGROUND: The high prevalence of cancer pain shows that a lot of the patients are undertreatment. Vitamin B is one of the additional alternative substances studied in cancer pain management. Thiamine is believed to modulate pain mechanisms in lowering the Cathecol-O-Methyltransferase (COMT) enzyme level. AIM: The aim of the study was to assess the correlation between Oral Thiamine as an Opioid Adjuvant and COMT Enzyme Levels in Cervical Cancer Patients METHODS: This research is a quasi-experimental study with a pre-test and post-test control group design. Patients in this study were 32 cervical cancer patients who experienced cancer pain, divided into two groups (treatment and control groups). The treatment group received morphine plus thiamine 500 mg/8 h/oral, and the control group received morphine alone. Measurement and evaluation of pain scores were carried out after 72 h of thiamine administration and blood collection was carried out again 4 h after the last thiamine administration to check thiamine levels and COMT. Then, data collection and analysis is being evaluated. RESULTS: From 32 cervical cancer patients studied, there were differences in changes in numeric rating scale (NRS) levels and COMT levels in the thiamine treatment group. CONCLUSIONS: The administration of thiamine can reduce COMT enzyme levels and clinically reduce NRS in cervical cancer patients. If it confirmed by other findings, thiamine might be considered for its use in the treatment of cancer pain.

Comparison of Bupivacaine with Two Different Doses of Clonidine under Spinal Anaesthesia in Infraumbilical SurgeriesA Randomised Clinical Study

Introduction: Spinal anaesthesia is known as a safe and effective way to give anaesthesia during infraumbilical and lower limb surgeries. Intrathecal clonidine is a safe non opioid adjuvant used with local anaesthetics to prolong sensory and motor block, promotes sedation and analgesia. Aim: To compare the effects of bupivacaine with two different doses of clonidine under spinal anaesthesia in infraumbilical surgeries. Materials and Methods: This randomised double-blinded study was conducted in the Department of Anaesthesiology at Hind Institute Of Medical Science, Sitapur, Uttar Pradesh, India. The duration of the study was 19 months, from January 2021 to August 2022. A total of 60 patients (36 males and 24 females) were enrolled in the study and were randomly assigned to one of two groups (group A and group B) of 30 patients each. Group A bupivacaine heavy 12.5 mg with 15 mcg of clonidine, total volume 3 mL and group B bupivacaine heavy 12.5 mg with 30 mcg of clonidine, total volume 3 mL. The study parameters were: onset of sensory and motor block, duration of postoperative analgesia and any side effects (hypotension, bradycardia, sedation or any other). The statistical analysis was done using Statistical Package for Social Sciences (SPSS) Version 21.0. Results: The mean age of the study participants group A (44.51±12.84) years and group B (42.28±13.12) years. The demographical data showed comparable findings. The mean of onset of sensory (160.37±33.64) seconds and motor block (197.2±12.36) seconds in group B was statistically lower than group A. The mean duration of analgesia in group A (302.58±18.62) minutes was lower than group B (318.73±29.46) minutes. The mean Visual Analogue Scale (VAS) score was higher at every follow-up in group A as compared to in group B. The mean Ramsay sedation score was significantly higher in Group B at every follow-up than in group A. Conclusion: Spinal anaesthesia performed with 0.5% bupivacaine heavy with 30 mcg clonidine was proven to be a more effective adjuvant in providing early onset of the sensory and motor blockade intraoperatively and prolongation of the duration of effective postoperative analgesia when compare to 15 mcg clonidine.

Novel N-normetazocine Derivatives with Opioid Agonist/Sigma-1 Receptor Antagonist Profile as Potential Analgesics in Inflammatory Pain.

Although opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common drugs used in persistent pain treatment; they have shown many side effects. The development of new analgesics endowed with mu opioid receptor/delta opioid receptor (MOR/DOR) activity represents a promising alternative to MOR-selective compounds. Moreover, new mechanisms, such as sigma-1 receptor (σ1R) antagonism, could be an opioid adjuvant strategy. The in vitro σ1R and σ2R profiles of previous synthesized MOR/DOR agonists (−)-2R/S-LP2 (1), (−)-2R-LP2 (2), and (−)-2S-LP2 (3) were assayed. To investigate the pivotal role of N-normetazocine stereochemistry, we also synthesized the (+)-2R/S-LP2 (7), (+)-2R-LP2 (8), and (+)-2S-LP2 (9) compounds. (−)-2R/S-LP2 (1), (−)-2R-LP2 (2), and (−)-2S-LP2 (3) compounds have Ki values for σ1R ranging between 112.72 and 182.81 nM, showing a multitarget opioid/σ1R profile. Instead, (+)-2R/S-LP2 (7), (+)-2R-LP2 (8), and (+)-2S-LP2 (9) isomers displayed a nanomolar affinity for σ1R, with significative selectivity vs. σ2R and opioid receptors. All isomers were evaluated using an in vivo formalin test. (−)-2S-LP2, at 0.7 mg/kg i.p., showed a significative and naloxone-reversed analgesic effect. The σ1R selective compound (+)-2R/S-LP2 (7), at 5.0 mg/kg i.p., decreased the second phase of the formalin test, showing an antagonist σ1R profile. The multitarget or single target profile of assayed N-normetazocine derivatives could represent a promising pharmacological strategy to enhance opioid potency and/or increase the safety margin.

Comparison of Fentanyl and Nalbuphine as an Adjuvant to Bupivacaine for Spinal Anesthesia in Lower Limb Surgeries

Background: Opioids commonly used as adjuvant anaesthetics during spinal anesthesia, are favored technique for lower limb surgeries. Nalbuphine is an opioid adjuvant that acts as antagonist at μ-receptors and agonist at k-receptors that work reasonably potent analgesia. In this study we compare the efficacy of epidural Fentanyl with bupivacaine versus Epidural Nalbuphine with Bupivacaine for post-operative pain relief in lower limb surgeries.
 Methods: Altogether 80 patients of lower limb surgeries were randomly allocated into two groups. 40 patients in Group I (Inj. 0.5% Bupivacaine (H) 2.5ml + Inj. Fentanyl 25mcg (0.5ml) and 40 patients in Group II (Inj. 0.5% Bupivacaine (H) 2.5ml+ Inj. Nalbuphine 5mg (0.5ml). Age of patients ranged from 18-65 years of age and male:female ratio in the present study was 1: 0.5. Patients in both the above groups were comparable on age, gender, anthropometric variables, and baseline hemodynamic variables.
 Results: In the study the mean age (36.30±14.10) of group II was comparatively more than the group I (33.88±9.42) while the mean weight (61.80±11.33) of group II was also comparatively more than group I mean weight (53.80±15.59). And the mean value of duration of surgery for the group I was (112.93±12.22) while it was (110.63±10.26) for group II. A significant difference was found in weight. The intergroup comparison of level of motor blockade where in group I the level of motor blockade was (65.0%) at 2 min (B/S-1) while in group II level of blockade (70.0%) at 2 min (B/S-1) after that from 8 min to 130 min it was (100%). The level of sensory blockade of group I (72.5%) at 2 min while it was (72.5%) at 6 min after that it was NA from 8 min to 130 min and in the group II level of sensory blockade (50.0%) at 2 min and (50.0%) at 8 min after that it was (100%) from 10 min to 130 min. During Intergroup Comparison of VAS significant differences was found at 30 min and 480 min.
 Conclusion: Nalbuphine when compared to Fentanyl is almost safe and hemodynamically stable drug that can be used as an adjuvant in combined spinal epidural anesthesia with similar safety profile as for Fentanyl.

Use of complementary and integrative health in cancer pain management among patients undergoing cancer treatments: a qualitative descriptive study.

Pain is a common symptom in patients undergoing cancer treatment. Despite recommendations for the stronger integration of complementary and integrative health (CIH) in cancer pain management, little is known about the individual experience of using this approach for cancer pain, particularly in certain populations such as African Americans. This study aimed to describe the experiences of using CIH for pain in African American and White patients with cancer undergoing cancer treatments. A secondary analysis of qualitative descriptive data from a subsample of patients with cancer in a parent study of their illness concerns was employed. Atlas.ti 8.0 was used for data management and qualitative analysis. Counts of participant-endorsed themes were tabulated to discern differences in themes by group. Of 32 participants (16 African American, 16 White), 22 reported CIH usage for cancer pain management, with equal distribution between groups (11 each). Three themes emerged: Approach to, Reasons for, and Barriers to CIH Use. Psychological approaches were most common (n = 15). Nutritional, physical, and combination approaches were less common and more often employed by White participants. Reasons for CIH use were to reduce opioid consumption or for an opioid adjuvant. Personal limitations and access issues contributed to Barriers to CIH use. Both African American and White patients used CIH for pain management while undergoing cancer treatments. However, some preferential differences in CIH approaches by race surfaced. Further research into these differences may uncover new ways of addressing disparities in cancer pain management with CIH.

Sex-specific role for serotonin 5-HT2A receptor in modulation of opioid-induced antinociception and reward in mice

Opioids are among the most effective analgesics and the mainstay of pain management. However, concerns about safety and abuse liability have challenged their widespread use by the medical community. Opioid-sparing therapies include drugs that in combination with opioids have the ability to enhance analgesia while decreasing opioid requirement as well as their side effects. Sex differences in antinociceptive responses to opioids have received increasing attention in recent years. However, the molecular mechanisms underlying sex differences related to opioid-sparing adjuncts remain largely unexplored. Using warm water tail-withdrawal as a mouse model of acute thermal nociception, our data suggest that adjunctive administration of the serotonin 5-HT2A receptor (5-HT2AR) antagonist volinanserin dose-dependently enhanced potency of the opioid analgesic oxycodone in male, but not female, mice. This antinociceptive-like response induced by oxycodone was also augmented in 5-HT2AR knockout (5-HT2AR−/−) male, but not female mice; an effect that was reversed by Cre-loxP-mediated selective expression of 5-HT2AR in dorsal root ganglion (DRG) neurons of 5-HT2AR−/− littermates. Pharmacological inhibition with volinanserin or genetic deletion in 5-HT2AR−/− animals potentiated the ability of oxycodone to reduce DRG excitability in male mice. Adjunctive volinanserin did not affect oxycodone-induced conditioned place preference (CPP), whereas it reduced oxycodone-induced locomotor sensitization in male and female mice. Together, these results suggest that adjunctive volinanserin augments opioid-induced antinociception, but not abuse-related behavior, through a sex-specific signaling crosstalk mechanism that requires 5-HT2AR expression in mouse DRG neurons. Ultimately, our results may pave the way for the clinical evaluation of volinanserin as a potential sex-specific opioid adjuvant.

Implementation of an Intravenous Lidocaine Guideline for Children and Adolescents with Sickle Cell Vaso-Occlusive Pain

IntroductionSickle cell disease (SCD) affects approximately 100,000 Americans.[1] Vaso-occlusive episodes (VOEs) are the leading cause of hospitalization in SCD; in 2016, out of 134,000 SCD hospitalizations, 81% included VOE. [2] Opioids are the mainstay of VOE treatment, but side effects include sedation, hyperalgesia, and dependency risk. Lidocaine, which inhibits voltage-gated sodium channels in peripheral sensory nerves, is given intravenously (IV) for postoperative pain management and holds promise for VOE treatment.[3]At St. Louis Children's Hospital (SLCH), children admitted with VOEs receive an opioid by continuous infusion plus patient-controlled analgesia (PCA) and non-opioid adjuvants. In 2019, the Sickle Cell Disease Program and Pain Management Service jointly developed a guideline for VOE management that includes:1. Standardized dosing of IV opioids and IV or oral NSAIDs2. Pain management service consultation for all children age ≥10 y admitted with VOE3. Initiation of IV lidocaine infusion (1-1.5 mg/kg/h x 48 h) within 24 h of admission for severe pain4. Addition of non opioid adjuvants, such as muscle relaxants, topical agents, and agents for neuropathic pain5. IV lidocaine is prescribed by the Pain Management Service. Patients are monitored for lidocaine side effects including tinnitus, perioral tingling, vital sign changes, and seizures. A 24 h serum lidocaine level is drawn to ensure levels are not supra-therapeutic.We aimed to evaluate the implementation of this care guideline, focused on IV lidocaine as a safe, tolerable and effective adjunct to opioids for VOE treatment in children.MethodsThis retrospective cohort study reviewed records of children with SCD age ≥10 years admitted for VOE at SLCH during 2018-2020. Data collected included patient demographics, impact on pain, lidocaine levels, and reported side effects. This study was approved by the institutional review board.ResultsWe identified 61 patients (31 males), median age 15.7 y (range 9-21), with 174 IV lidocaine administrations during 164 hospitalizations. Hemoglobin (Hb) SS comprised 60.7% of the cohort; 32.8% had Hb SC disease, 4.9% had Hb Sβ0 thalassemia and 1.6% had Hb Sβ+ thalassemia. IV lidocaine was started within 24 h for 78.7% (129/164) of included admissions. The mean blood lidocaine level was 2.14 mcg/ml (SD 1.23). Of the 164 admissions, 9 individuals had lidocaine levels above the limit of 4.5 mcg/ml, none had symptoms of toxicity. Few side effects were noted: lip paresthesia in 1 child (lidocaine stopped, but received in future admissions); nausea in 1 child (declined lidocaine in future admissions); pain increase in 1 teen (lidocaine was stopped). One child stopped lidocaine infusions prematurely during 2 admissions due to refusal of phlebotomy for the lidocaine level. Overall, 59 children perceived benefit of IV lidocaine and chose to receive it again during later admissions. During 10 prolonged hospitalizations, a second 48-hour lidocaine infusion was given due to patient reported benefit.We identified falsely elevated lidocaine levels when subcutaneous lidocaine was used before phlebotomy, but no patients with high lidocaine levels experienced toxicity. We altered our response to supratherapeutic levels by pausing the lidocaine infusion, redrawing lab at a peripheral site without subcutaneous lidocaine contamination, and resuming lidocaine infusion if level was normal. Every repeated lidocaine level was within normal limits.DiscussionIn our cohort, IV lidocaine was safe, tolerable, and improved pain control. The care guideline was initiated within 24 hours for 78.7% of admissions. Mild side effects occurred in only 3 patients, highlighting safety. Future considerations include a prospective study focused on length of stay, patient-reported outcomes, opioid exposure, and factors influencing the care guideline's utilization.

The Density of Different Local Anesthetic Solutions, Opioid Adjuvants and Their Clinically Used Combinations: An Experimental Study.

Various opioids are added to local anesthetic solutions for spinal anesthesia. This may change the final density of the local anestetic (LA) mixture. This effect regarding current concepts in spinal anesthesia needs to be re-evaluated. In order to re-evaluate such effects, hyperbaric and isobaric local anesthetic (LA) solutions were mixed with opioid adjuvants (A) using the equipment available in the operating room. Ten density measurements for each composition (LA-A) were performed. The density change of 0.0006 g/mL was regarded as significant. Measured densities were also compared with theoretical values calculated using Hare’s. As a result, the addition of an opioid adjuvant caused a significant reduction in the final density of the LA-A solution. In hyperbaric LA mixtures, it did not change the baricity from hyperbaric to isobaric. However, the addition of highly hypobaric fentanyl 0.99360 g/mL (SD ± 0.00004) changes all isobaric LA solutions baricity to hypobaric. The comparison of measured and theoretical densities revealed significant differences (p > 0.05). However, the absolute reduction reached 0.0006 g/mL in only two LA-A compositions. We conclude that the addition of fentanyl to isobaric LA results in a hypobaric solution that may affect the distribution of the block. The inadequacy of LA-A in a clinical setting is unlikely to influence block characteristics.

Enhancement of Opioid Antinociception by Nicotine.

Nicotine can produce antinociception in preclinical pain models; however, the ability of nicotine to augment the antinociceptive effects of opioid agonists has not been investigated. The present experiments were conducted to determine how nicotine modifies the effects of opioid agonists differing in efficacy. Male squirrel monkeys responded for the delivery of milk under a fixed ratio 10 schedule of reinforcement. During the 30-second timeout period following each milk delivery, the subject's tail was immersed in 35, 50, 52, or 55°C water, and the latency to remove the tail was recorded. Dose-response functions for tail-withdrawal latency and operant performance were determined for fentanyl, oxycodone, buprenorphine, and nalbuphine alone and after treatment with nicotine. Excepting nalbuphine, all opioids produced dose-related disruptions in food-maintained responding and increases in tail-withdrawal latency at each water temperature. Nicotine did not exacerbate the behaviorally disruptive effects of the μ-opioids on operant performance but produced a significant mecamylamine-sensitive enhancement of the antinociceptive potency of each opioid. Failure of arecoline to augment the antinociceptive effects of oxycodone and antagonism by mecamylamine suggests this nicotine-induced augmentation of prescription opioid antinociception was nicotinic acetylcholine receptor (nAChR) mediated. This was reflected in leftward shifts in the antinociceptive dose-response curve of each opioid, ranging from 2- to 7-fold increases in the potency of oxycodone across all water temperatures to an approximately 70-fold leftward shift in the antinociceptive dose-response curve of nalbuphine at the lower and intermediate water temperatures. These results suggest that nicotine may enhance μ-opioid antinociceptive effects without concomitantly exacerbating their behaviorally disruptive effects. SIGNIFICANCE STATEMENT: Prescription opioids remain the most effective pain-management pharmacotherapeutics but are limited by their adverse effects. The present results indicate that nicotine enhances antinociceptive effects of various opioid agonists in nonhuman primates without increasing their disruptive effects on operant performance. These results suggest that nicotine might function as an opioid adjuvant for pain management by enabling decreased clinically effective analgesic doses of prescription opioids without exacerbating their adverse behavioral effects.

Cannabinoid modulation of opioid analgesia and subjective drug effects in healthy humans.

Dozens of preclinical studies have reported cannabinoid agonist potentiation of the analgesic effects of μ-opioid agonists. The aim of this study was to determine if a cannabinoid agonist could potentiate opioid analgesia in humans using several laboratory pain models. Healthy participants (n = 10) with/out current drug use/pain conditions completed this within-subject, double-blind, placebo-controlled, randomized outpatient study. Nine 8-h sessions were completed during which dronabinol (0, 2.5, 5mg, p.o.) was administered 1h before oxycodone (0, 5, 10mg, p.o.) for a total of 9 test conditions. Outcomes included sensory threshold and tolerance from four experimental pain models (cold pressor, pressure algometer, hot thermode, cold hyperalgesia), along with participant- and observer-rated, performance and physiological effects. Oxycodone produced miosis (p < 0.05) and analgesic responses (e.g., pressure algometer [p < 0.05]), while dronabinol did not (p > 0.05). Depending on the dose combination, dronabinol attenuated or did not alter oxycodone analgesia; for example, dronabinol (2.5mg) decreased the analgesic effects of oxycodone (10mg) on pressure tolerance. Conversely, dronabinol increased oxycodone subjective effects (e.g., drug liking) (p < 0.05); oxycodone (5mg) ratings of "high" were potentiated by 5mg dronabinol (p < 0.05; placebo = 1.1 [± 0.7]; 5mg oxycodone = 4.7 [± 2.2]; 5mg dronabinol = 9.9 [± 8.4]; 5mg oxycodone + 5mg dronabinol = 37.4 [± 11.3]). This study indicates that dronabinol did not enhance the analgesic effects of oxycodone and increased abuse- and impairment-related subjective effects. These data suggest that dronabinol may not be an effective or appropriate opioid adjuvant; it could potentially increase opioid dose requirements, while increasing psychoactive opioid effects.

Comparison of dexmedetomidine v/s buprenorphine as an adjuvant to levobupivacaine in spinal anesthesia for infraumbilical surgeries

Background: There has been a constant research towards the invention of adjuvants to local anesthetics in spinal anesthesia so as to improve the efficacy, minimize the side effects and to provide excellent perioperative analgesia. In this journey, the invention of non-opioid adjuvants to replace the most popular opioid adjuvant has taken a lead role. With this background, in our study we have compared Dexmedetomidine with Buprenorphine as an adjuvant to 0.5% levobupivacaine in spinal anesthesia in patients undergoing infraumbilical surgeries. Methods: Sixty patients randomly allocated to two groups wherein Group LD received 5 mcg of dexmedetomidine with 15mg of 0.5% Levobupivacaine and Group LB received 75 mcg of Buprenorphine with 15 mg of 0.5% Levobupivacaine. Results: There was no significant difference in the onset time of sensory and motor block in group LD and group LB. The duration of sensory and motor block is statistically significantly prolonged in Group LD as compared to Group LB. Degree of Sedation was better in Group LD when compared with Group LB. Hemodyanamic stability was preserved in both the groups. The time for first rescue analgesia was significantly prolonged in Group LD compared to Group LB. Conclusion: Dexmedetomidine as an adjuvant to 0.5% levobupivacaine in spinal anesthesia produces longer duration of sensory and motor block but takes slightly more time to attain complete motor block as compared to Buprenorphine. Dexmedetomidine also provides an additional benefit of providing conscious sedation with fewer side effects.

Caffeine as an opioid analgesic adjuvant in fibromyalgia.

BackgroundCaffeine’s properties as an analgesic adjuvant with nonsteroidal anti-inflammatory drugs/acetaminophen are well documented. However, little clinical research has explored caffeine’s effects on opioid analgesia. This study assessed the effects of caffeine consumption on pain and other symptoms in opioid-using and nonusing chronic pain patients meeting the survey criteria for fibromyalgia.Materials and methodsPatients presenting to a university-based pain clinic completed validated self-report questionnaires assessing symptoms. Patients (N=962) meeting the fibromyalgia survey criteria were stratified by opioid use and further split into groups based on caffeine amount consumed per day (no caffeine, or low, moderate, high caffeine). Analysis of covariance with Dunnett’s post hoc testing compared pain and symptom severity between the no caffeine group and the caffeine consuming groups.ResultsIn opioid users, caffeine consumption had modest but significant effects on pain, catastrophizing, and physical function. Lower levels of pain interference were associated with low and moderate caffeine use compared to no caffeine intake. Lower pain catastrophizing and higher physical function were observed in all caffeine dose groups, relative to the no caffeine group. Lower pain severity and depression were observed only in the moderate caffeine group. In opioid nonusers, low caffeine intake was associated with higher physical function; however, no other significant effects were observed.ConclusionCaffeine consumption was associated with decreased pain and symptom severity in opioid users, but not in opioid nonusers, indicating caffeine may act as an opioid adjuvant in fibromyalgia-like chronic pain patients. These data suggest that caffeine consumption concomitant with opioid analgesics could provide therapeutic benefits not seen with opioids or caffeine alone.

Opioid adjuvant strategy: improving opioid effectiveness.

Opioid analgesics continue to be the mainstay of pharmacologic treatment of moderate to severe pain. Many patients, particularly those suffering from chronic pain, require chronic high-dose analgesic therapy. Achieving clinical efficacy and tolerability of such treatment regimens is hampered by the appearance of opioid-induced side effects such as tolerance, hyperalgesia and withdrawal syndrome. Among the therapeutic options to improve the opioid effectiveness, this current review focuses on strategies combining opioids to other drugs that can modulate opioid-mediated effects. We will discuss about experimental evidences reported for several potential opioid adjuvants, including N-methyl-D-aspartate receptor antagonists, 5-HT7 agonists, sigma-1 antagonists, I2-R ligands, cholecystokinin antagonists, neuropeptide FF-R antagonists and toll-like receptor 4 antagonists.

Selective sigma-1 receptor antagonists for the treatment of pain.

The sigma-1 receptor (σ1R) is located in areas of the CNS key for pain control and belongs to a unique target class with chaperoning functions over different molecular targets involved in transmission and amplification of nociceptive messages. Preclinical evidence supports a role for σ1R antagonists in the treatment of pain states where hypersensitivity develops as hyperalgesia and allodynia, two common symptoms encountered in neuropathic and other chronic pain conditions. Additionally, σ1R antagonists increase opioid analgesia without increasing opioid-related unwanted effects, which point to their potential use as opioid adjuvant therapy. This review summarizes the structure and function of the σ1R as well as the medicinal chemistry and pharmacological studies directed to the identification of σ1R antagonists for the treatment of pain.

Comparison of intraoperative blood loss during spinal surgery using either remifentanil or fentanyl as an adjuvant to general anesthesia

BackgroundRemifentanil enhances intraoperative hemodynamic stability, suggesting that it may decrease intraoperative blood loss when included as an adjuvant to general anesthesia. This retrospective study compared intraoperative blood loss during spinal surgery in patients administered either remifentanil or fentanyl as an opioid adjuvant.MethodsWe reviewed clinical and surgical data from 64 consecutive laminoplasty or laminectomy patients treated at National Hospital Organization Zentsuji Hospital between April 2010 and March 2011. Patients received either remifentanil (n = 35) or fentanyl (n = 29) as an opioid analgesic during general anesthesia. In addition to intraoperative blood loss, indices of hemodynamic stability, including heart rate as well as systolic, mean, and diastolic blood pressure (BP), were compared over the entire perioperative period between remifentanil and fentanyl groups.ResultsThe remifentanil group exhibited significantly lower intraoperative arterial BP than the fentanyl group. Intraoperative blood loss was also significantly lower in the remifentanil group (125 ± 67 mL vs. 165 ± 82 mL, P = 0.035).ConclusionsIntraoperative blood loss during spinal surgery was decreased in patients who received remifentanil as an opioid adjuvant, possibly because of lower intraoperative BP. A larger-scale prospective randomized controlled trial is warranted to confirm our results and to test whether remifentanil can decrease intraoperative blood loss during other surgical procedures.

Sigma-1 receptor antagonism as opioid adjuvant strategy: Enhancement of opioid antinociception without increasing adverse effects

While opioids are potent analgesics widely used in the management of pain, a number of well-known adverse effects limit their use. The sigma-1 receptor is a ligand-regulated molecular chaperone involved in pain processing, including modulation of opioid antinociception. However, data supporting the potential use of sigma-1 receptor ligands as suitable opioid adjuvants are based on studies that use non selective ligands. Also, safety issues derived from combination therapy are poorly addressed. In this study we used the new selective sigma-1 receptor antagonist S1RA (E-52862) to characterize the effect of selective sigma-1 receptor blockade on opioid-induced efficacy- and safety-related outcomes in mice. S1RA (40mg/kg) had no effect in the tail-flick test but did enhance the antinociceptive potency of several opioids by a factor between 2 and 3.3. The potentiating effect of S1RA on morphine antinociception did not occur in sigma-1 receptor knockout mice, which supports the selective involvement of the sigma-1 receptor. Interestingly, S1RA co-administration restored morphine antinociception in tolerant mice and reverted the reward effects of morphine in the conditioned place preference paradigm. In addition, enhancement of antinociception was not accompanied by potentiation of other opioid-induced effects, such as the development of morphine analgesic tolerance, physical dependence, inhibition of gastrointestinal transit, or mydriasis. The use of sigma-1 receptor antagonists as opioid adjuvants could represent a promising pharmacological strategy to enhance opioid potency and, most importantly, to increase the safety margin of opioids. S1RA is currently in phase II clinical trials for the treatment of several pain conditions.

Alternative forms of interaction of substance P and opioids in nociceptive transmission

Many years preclinical and clinical anatomic, pharmacologic, and physiologic studies suggest that SP- and opioid-expressing neurons produce opposite biological effects at the spinal level, i.e., nociception and antinociception, respectively. However, in certain circumstances intrathecally administered SP is capable of reinforcing of spinal morphine analgesia and may therefore function as an opioid adjuvant in vivo. The SP dose-response curve of spinally administered SP follows a bell-shaped or inverted-U configuration, permitting pharmacological dissociation of opioid-potentiating and analgesic properties of SP from traditional hyperalgesic effects seen at significantly higher concentrations. This analgesic effect is blocked by naloxone but unaffected by transection of the spinal cord, thus demonstrating the lack of supraspinal modulation. The present report briefly describes both reinforcing and opposing interactions between multiple opioid systems and substance P at the spinal level. We propose that a likely mechanism underlying SP-mediated enhancement of opioid analgesia is the ability of SP to release endogenous opioid peptides within the local spinal cord environment.