New concepts in opioid analgesia

ABSTRACT

Introduction: Opioids are the oldest and most potent drugs for the treatment of severe pain, but they are burdened by detrimental side effects such as respiratory depression, addiction, sedation, nausea, and constipation. Their clinical application is undisputed in acute (e.g. perioperative) and cancer pain, but their long-term use in chronic pain has met increasing scrutiny and has contributed to the current ‘opioid crisis.’

Areas covered: This article reviews pharmacological principles and research strategies aiming at novel opioids with reduced side effects. Basic mechanisms underlying pain, opioid analgesia, and other opioid actions are outlined. To illustrate the clinical situation and medical needs, plasticity of opioid receptors, intracellular signaling pathways, endogenous and exogenous opioid receptor ligands, central and peripheral sites of analgesic, and side effects are discussed.

Expert opinion: The epidemic of opioid misuse has taught us that there is a lack of fundamental knowledge about the characteristics and management of chronic pain, that conflicts of interest and validity of models must be considered in the context of drug development, and that novel analgesics with less abuse liability are badly needed. Currently, the most promising perspectives appear to be augmenting endogenous opioid actions and selectively targeting pathological conformations of peripheral opioid receptors.     

State of the art opioid-sparing strategies for post-operative pain in adult surgical patients

Introduction: There are various important implications associated with poorly controlled postoperative pain in the adult surgical patient – this includes cardiopulmonary complications, opioid-related side effects, unplanned hospital admissions, prolonged hospital stay, and the subsequent development of chronic pain or opioid addiction. With the ongoing national opioid crisis, it is imperative that perioperative providers implement pathways for surgical patients that reduce opioid requirements and pain-related complications.

Areas covered: In this review, the authors discuss the components of a multimodal opioid-sparing analgesia pathway as it pertains to the perioperative environment. Medications reviewed include gabapentinoids, acetaminophen, non-steroidal anti-inflammatory drugs, ketamine, intravenous lidocaine, dexmedetomidine, and glucocorticoids. The use of peripheral nerve blocks and neuraxial analgesia are also discussed.

Expert opinion: In appropriate cases, regional anesthetic interventions are extremely useful for postoperative analgesia, including peripheral nerve blocks and neuraxial analgesia and while newer postoperative analgesics have been postulated, the literature on such is presently controversial. Coordinated approaches to pain management are recommended to reduce the need for opioids and to improve patient satisfaction post-surgery.     

Pain management in opioid maintenance treatment

ABSTRACT

Introduction: Opioid addiction is a worldwide disease with a significant impact. A multitude of physical and mental comorbidities are associated with opioid addiction, pain being one of the most relevant. Insufficient pain management may lead to a disruption in medical treatment, self-medication, and subsequent harm to patients.

Areas covered: In this review, the authors provide a general overview of opioid addiction. A literature search for pain management and opioid maintenance treatment was conducted. Different settings of acute or chronic pain and situations specific to patients addicted to opioids are described. Pain management therapy in addiction is also addressed with an emphasis on treatment strategies such as the optimization of methadone and buprenorphine medication, additional opioid analgesia, and multimodal pain management.

Expert opinion: Opioid addiction is a growing global health concern, and maintenance therapy remains an effective and lifesaving treatment option. However, there remains uncertainty on the appropriate pain management for this patient group. The backbone of pain management in opiate-addicted patients remains maintenance therapy while adjunctive treatment such as regional analgesia, non-opioid analgesia, antidepressants, steps to improve sleep, acceptance and commitment therapy, biofeedback, and hypnosis should be considered. Additional opioid medication is possible as well.     

Pharmacokinetic and pharmacodynamic evaluation of sublingual sufentanil in the treatment of post-operative pain

Introduction: Intravenous patient-controlled analgesia using opioids is frequently used to provide perioperative analgesia. However, there are a number of drawbacks for intravenous patient-controlled analgesia. The sufentanil sublingual tablet system is a major evolution in technology and drug development for postoperative pain management.

Areas Covered: We reviewed the use of sublingual sufentanil in postoperative pain management, with a focus on chemistry, pharmacokinetics and clinical use in different surgical patients.

Expert Opinion: The sufentanil sublingual tablet system can decrease intravenous patient-controlled analgesia-related safety issues. Current clinical studies have demonstrated this novel system to be safe and effective in postoperative pain management.     

Sufentanil sublingual tablet system for the management of postoperative pain

Introduction: Intravenous patient-controlled opioid analgesia has been an important improvement in addressing insufficient management of acute postoperative pain for over 40 years. However, there are number of weaknesses for intravenous patient-controlled analgesia, including operator and device error, intravenous line patency issues, and risk of catheter-related infection, all of which contribute to the complications and increase in cost of care. The sublingual sufentanil tablet system is a major evolution in both drug and technological management of postoperative pain.

Areas covered: We reviewed the use of the sublingual sufentanil tablet system in management of moderate to severe postoperative pain in hospitalized patients, with a particular focus on the pharmacological properties of sufentanil and clinical use in different surgical patients.

Expert opinion: The sublingual sufentanil tablet system can decrease intravenous opioid based patient-controlled analgesia related complications and safety issues. Current clinical studies have demonstrated this noninvasive-novel system to be safe and effective in management of acute pain in the postsurgical setting. Researchers should focus on comparing it with other available patient controlled analgesia modalities and evaluating the efficiency and cost effectiveness of the sublingual sufentanil tablet system.     

Emerging infectious diseases - a therapeutic challenge

Introduction: Despite its central role in acute pain management, the exclusive use of opioids has been challenged recently in view of its immediate and long-term side effects. Development of chronic postsurgical pain syndromes, hyperalgesia and immunomodulation are some particular concerns as they may be related to opioid exposure, intertwined with patient characteristics and other factors. Application of a multimodal approach, administration of preventive analgesia and paradigm shift in surgical techniques all mandate a revisit of evidence-based perioperative pain management.

Areas covered: Adjuvant analgesics are drugs indicated for primary non-pain conditions, but have been found efficacious in analgesia either when used alone or in combination with other analgesics. Among a diverse group of adjuvant analgesics, systemic administration of ketamine, magnesium, gabapentinoids, steroids, α2 agonists and lidocaine are reviewed, with recent evidence compared with earlier systematic reviews or meta-analyses from a Medline search (1990 – Apr 2010).

Expert opinion: For acute pain management, adjuvant analgesics in appropriate doses and monitored care are beneficial in improving analgesic efficacy and reduce opioid-related side effects with good safety and tolerability. However, the quest for an optimal regime for administration and individualizing treatment remains.     

Opioid switching and rotation in primary care: implementation and clinical utility

ABSTRACT

Background: Opioid therapy is the standard treatment for moderate-to-severe cancer pain and is becoming a more frequent treatment for moderate-to-severe chronic noncancer pain. Response to opioids varies significantly between patients and even within the individual patient at different stages of treatment. Finding an opioid at a dose that provides adequate long-term analgesia with minimal adverse effects can be difficult. Opioid switching and opioid rotation, at different stages of therapy, represent two clinical strategies used to optimize opioid response for patients with moderate-to-severe pain.

Objectives: Review the theoretical and clinical evidence supporting the concepts of opioid switching and rotation, outline the conditions under which these practices should be considered, and briefly suggest practical steps for their implementation

Scope: Clinical literature, clinical practice and guideline databases, and professional society websites were searched for articles or reports describing opioid switching or opioid rotation in chronic pain therapy; variability in patient response to opioid therapy; physiologic, pharmacologic, and genetic factors that affect clinical response to opioids; and practical approaches to maximizing analgesia and minimizing adverse effects in opioid therapy. It is outside the scope of this review to evaluate the pharmacoeconomic aspects that affect changes in opioid therapy.

Findings: The variability in de novo clinical response to opioids likely represents the interaction of the varying properties of the individual opioids with the variability in individual patient biology. This interaction forms the rationale for opioid switching and explains its clinical utility. As with opioid switching, success with opioid rotation is related to the myriad of factors determining an individual patient's response to a specific opioid. However, the benefits of opioid rotation also derive from a partial reversal of tolerance at the μ-opioid receptor and the response of different μ-opioid receptor subtypes to the different opioids.     

单剂量酮咯酸用于围术期超前镇痛的meta分析

目的 采用meta分析综合评价单剂量酮咯酸用于围术期超前镇痛的有效性及安全性。方法 遵循PRISMA声明指南,全面检索公开发表的随机对照试验,通过meta分析综合评价单剂量全身酮咯酸对术后疼痛、阿片样药物消耗及不良反应的影响。结果 共纳入11项研究,累计606人。Meta分析结果表明术后0,4,8 h的酮咯酸超前镇痛效果明显,术后24 h的酮咯酸超前镇痛效果无统计学差异。酮咯酸超前镇痛可以减少术后阿片类药物（吗啡）的使用[MD=-4.25,95%CI （-8.16,-0.35）,P=0.03],减少恶心、呕吐不良反应的发生[RR=0.68,95%CI （0.51,0.90）,P=0.006],且未增加严重不良反应。结论 现有的临床文献数据表明,酮咯酸用于围手术期超前镇痛效果明确,可减少术后阿片类药物（吗啡）的使用量,同时减少了恶心或呕吐的发生。     

Non-invasive patient-controlled analgesia in the management of acute postoperative pain in the hospital setting

Objective: Acute postoperative pain is experienced by the majority of hospitalized patients undergoing surgical procedures, with many reporting inadequate pain relief and/or high levels of dissatisfaction with their pain management. Patient-controlled analgesia (PCA) ensures patient involvement in acute pain control, a key component for implementing a quality management system. This narrative article overviews the clinical evidence for conventional PCA and briefly discusses new, non-invasive PCA systems, namely the sufentanil sublingual tablet system (SSTS) and the fentanyl iontophoretic transdermal system (FITS).

Methods: A Medline literature search (“patient-controlled analgesia” and “acute postoperative pain”) was conducted to 1 April 2017; results from the main clinical trials are discussed. Additional literature was identified from the reference lists of cited publications.

Results: Moderate to low quality evidence supports opioid-based intravenous PCA as an efficacious alternative to non-patient-controlled systemic analgesia for postoperative pain. However, despite the benefits of PCA, conventional intravenous PCA is limited by system-, drug- and human-related issues. The non-invasive SSTS and FITS have demonstrated good efficacy and safety in placebo- and intravenous morphine PCA-controlled trials, and are associated with high patient/healthcare practitioner satisfaction/ease of care ratings and offer early patient mobilization.

Conclusions: Evidence-based guidelines for acute postoperative pain management support the use of multimodal regimens in many situations. As effective and safe alternatives to conventional PCA, and with the added benefits of being non-invasive, easy to use and allowing early patient mobilization, the newer PCA systems may complement multimodal approaches, or potentially replace certain regimens, in hospitalized patients with acute postoperative pain.     

Nav1.7 and other voltage-gated sodium channels as drug targets for pain relief

Introduction: Chronic pain is a massive clinical problem. We discuss the potential of subtype selective sodium channel blockers that may provide analgesia with limited side effects.

Areas covered: Sodium channel subtypes have been linked to human pain syndromes through genetic studies. Gain of function mutations in Na_v1.7, 1.8 and 1.9 can cause pain, whilst loss of function Na_v1.7 mutations lead to loss of pain in otherwise normal people. Intriguingly, both human and mouse Na_v1.7 null mutants have increased opioid drive, because naloxone, an opioid antagonist, can reverse the analgesia associated with the loss of Na_v1.7 expression.

Expert Opinion: We believe there is a great future for sodium channel antagonists, particularly Na_v1.7 antagonists in treating most pain syndromes. This review deals with recent attempts to develop specific sodium channel blockers, the mechanisms that underpin the Na_v1.7 null pain-free phenotype and new routes to analgesia using, for example, gene therapy or combination therapy with subtype specific sodium channel blockers and opioids. The use of selective Na_v1.7 antagonists together with either enkephalinase inhibitors or low dose opioids has the potential for side effect-free analgesia, as well as an important opioid sparing function that may be clinically very significant.     

骶骨肿瘤切除术围术期疼痛及管理现状分析

目的　调查骶骨肿瘤切除术围术期疼痛现状和镇痛策略,探索围术期镇痛管理中可改进的方面。方法　回顾性分析2018年1月—2019年12月行骶骨肿瘤切除术患者的临床资料。主要观察指标包括术后疼痛程度及术后阿片类药物用量,次要指标包括术前疼痛及阿片类药物使用情况、术中及术后镇痛方案、术后住院时间及手术并发症等。结果　共纳入215例骶骨肿瘤手术患者,其中术前存在慢性疼痛者126例（58.6%）,术前使用阿片类药物者49例（22.8%）。术中及术后镇痛以单一阿片类药物镇痛模式为主。术后第1天中、重度疼痛者112例（53.3%）,疼痛程度与患者术前疼痛情况及阿片类药物使用情况、肿瘤位置、肿瘤切除方式等均无相关性（P＞0.05）。术后阿片类药物用量与疼痛程度正相关（P＜0.05）。术后7 d仍需服用阿片类药物者占42.3%,出院时降至26.0%。术后住院时间与术后疼痛程度呈正相关（P＜0.05）。与术前未使用阿片类药物者相比,术前使用阿片类药物者术后7 d累积阿片类用量、术后7 d及出院时仍需服用阿片类药物者比例显著增高（P＜0.05）。结论　骶骨肿瘤患者术前疼痛发生率高,术后疼痛剧烈,阿片类药物需求量大,需要进一步优化镇痛模式,改进术后镇痛管理质量。     

Hospital admission medication reconciliation in high-risk prescription opioid users

BackgroundNo studies have assessed the clinical significance of medication reconciliation in surgical patients using high-risk extended-release/long-acting (ER/LA) opioid medications.ObjectivesWe assessed differences in the perioperative use of opioid analgesics in patients who underwent medication reconciliation upon hospital admission compared to patients who did not and identified predictors of perioperative use of opioids.MethodsRetrospective observational quasi-experimental study including adult non-cancer patients who underwent elective surgery at UCSF Medical Center in the period January 2017 through December 2019 and received at least one opioid analgesic during surgical hospitalization. The primary study outcome was perioperative use of opioids measured in daily oral morphine equivalents (OME). Secondary outcomes were predictors of perioperative use of opioids after adjusting for baseline differences between groups.ResultsWe identified 402 patients. Of them, 59.5% were female. The mean patient age was 58.5 years. Most patients underwent neurological or orthopedic surgery (each 40.8%). Over 94.3% of our patients underwent medication reconciliation upon hospital admission, with 78.4% completed by a pharmacy staff. Medication reconciliation evidenced that 5.5% patients were not taking the ER/LA opioids on their medication history list. Inactive ER/LA opioids were discontinued during hospitalization. None of the patients with inactive ER/LA opioids had those opioids restarted at hospital discharge. In addition, patients (26.9%) were successfully converted from ER/LA to SA opioids. After adjusting for patients’ demographic and clinical characteristics, surgical procedure type and post-operative pain, opioid formulation conversion was the main predictor of perioperative use of opioids per hospitalization day. Switching patients from ER/LA to SA opioids reduced the mean daily use of OME by 66.03 units (p < 0.02) without adversely impacting postoperative pain.ConclusionsMedication reconciliation upon hospital admission reduced unnecessary exposure to opioids in hospitalized surgical patients.     

Chronic pain management issues in the primary care setting and the utility of long-acting opioids

Importance of the field: Chronic/persistent pain – a highly prevalent condition that places a substantial burden on patients in terms of personal suffering, reduced productivity and health care costs – remains inadequately treated in many patients. The purpose of this review is to provide an overview and evaluate the burden and undertreatment of chronic/persistent pain, considerations for choosing an analgesic and the utility of long-acting opioids.

Areas covered in this review: A PubMed search was conducted to identify randomized, placebo-controlled trials evaluating the efficacy and safety of long-acting opioids in chronic pain conditions. The following search terms were used: long-acting opioids, extended-release opioids, controlled-release opioids, sustained-release opioids, and transdermal opioids. The search was limited to randomized, controlled trials published within the last 10 years (1998 – 2008). Studies meeting the following criteria were excluded from review: those focused on a neuropathic pain condition or specific patient subpopulations (e.g., opioid-experienced patients); those conducted outside the USA; and those evaluating a long-acting opioid that is not on the US market at present.

What the reader will gain: The reader will first develop a better understanding of the individual and societal ramifications of undertreated chronic pain. Then, a critical review of safety and efficacy data from well-controlled randomized studies will help readers understand the choices and variables that should be considered when selecting appropriate treatments for patients with chronic pain.

Take home message: Successful management of chronic/persistent pain should be individually tailored to each patient, taking into account his or her pain intensity and duration, disease state, tolerance of adverse events and risk of medication abuse or diversion. The literature supports the efficacy and safety of a number of long-acting opioids for the treatment of moderate to severe chronic pain, demonstrating sustained improvements in pain intensity and pain-related sleep disturbances with these agents.     

Pregabalin for the treatment of postsurgical pain

Importance of the field: Multimodal postoperative pain management targeted at diminishing harmful outcomes should include pregabalin in cases that need opioid reduction and when the risk of developing chronic neuropathic postsurgical pain is present. Gabapentanoids have grown in importance due to their opioid-sparing effects. They may also contribute to the prevention of chronic postsurgical pain.

Areas covered in this review: We reviewed the literature regarding the use of gabapentanoids and their role in treatment modalities in acute postsurgical pain. Dosing, therapeutic efficacy, side effects, and their role within a multimodal regimen are discussed. Particular emphasis is placed on their ability to provide an opioid-sparing effect, as well as on their potential for inhibiting chronic neuropathic pain. A Pubmed search of pregabalin, gabapentin, acute pain, multimodal analgesia, chronic postsurgical pain, and neuropathic pain between 2000 and 2010 was done. Relevant articles – including randomized controlled trials, retrospective trials, case series, case reports, and review articles – were filtered to include those that relate to postsurgical pain.

What the reader will gain: Readers will gain an increased appreciation of the role of pregabalin in postsurgical pain in patients at risk of developing chronic pain.

Take home message: Pregabalin is a safe and effective medication that may decrease perioperative opioid use in patients with more acute neuropathic pain than acute inflammatory pain. When surgery involves more neuropathic-type acute pain there is growing evidence that pregabalin may decrease the incidence of chronic pain.     

Mechanistic and functional differentiation of tapentadol and tramadol

Introduction: Many opioid analgesics share common structural elements; however, minor differences in structure can result in major differences in pharmacological activity, pharmacokinetic profile, and clinical efficacy and tolerability.

Areas covered: This review compares and contrasts the chemistry, pharmacodynamics, pharmacokinetics, and CNS ‘functional activity' of tapentadol and tramadol, responsible for their individual clinical utilities.

Expert opinion: The distinct properties of tapentadol and tramadol generate different CNS functional activities, making each drug the prototype of different classes of opioid/nonopioid analgesics. Tramadol's analgesia derives from relatively weak µ-opioid receptor (MOR) agonism, plus norepinephrine and serotonin reuptake inhibition, provided collectively by the enantiomers of the parent drug and a metabolite that is a stronger MOR agonist, but has lower CNS penetration. Tapentadol's MOR agonist activity is several-fold greater than tramadol's, with prominent norepinephrine reuptake inhibition and minimal serotonin effect. Accordingly, tramadol is well-suited for pain conditions for which a strong opioid component is not needed—and it has the benefit of a low abuse potential; whereas tapentadol, a schedule-II controlled substance, is well-suited for pain conditions requiring a strong opioid component—and it has the benefit of greater gastrointestinal tolerability compared to classical strong opioids. Both drugs offer distinct and complementary clinical options.