Postoperative analgesia in patients with substance use disorders: Part I

The specific problems related to postoperative analgesia in patients with substance use disorders (SUD) concerning opioids, alcohol, benzodiazepines, barbiturates, cocaine, crack, amphetamines, amphetamine-like designer drugs (MDMA, ecstasy), LSD, and marijuana are described. Whereas SUD with only one substance rarely occurs, the number of polysubstance abusers is increasing. Patients with SUD may have multiple organic diseases, impaired immune response, psychiatric and behavioural abnormalities and substance-induced disorders (intoxication, withdrawal, delerium, psychotic disorders), often associated with low compliance and craving behaviour.The perioperative management should be focused on three problems: (1) on the prevention of physical withdrawal symptoms and stressful complications in patients with SUD using CNS-depressants, (2) on the symptomatic treatment of the predominant affective withdrawal symptoms in patients suffering from SUD with CNS-stimulants, and (3) on the effective pain treatment.The analgesic therapy is often difficult and required for longer periods of time than in other patients. However, the principles of multimodal analgesia are as valid as in non-addicts. To be effective, systemic analgesia with paracetamol, NSAIDs and opioids has to be adapted as usual, but regional analgesia techniques should be preferred for postoperative pain relief.Patients enrolled in preoperative maintenance programmes (methadone, buprenorphine) need their daily maintenance dose as baseline. Ths baseline therapy does not, however, induce analgesia. Therefore, these patients need additional short-acting opioids which have to be administered at higher doses than usual (which do not cause respiratory depression due to opioid tolerance). The additional opioid does not increase the risk of relapse into active SUD. On the other hand, regional analgesia in patients who are enrolled in a maintenance programme does not mean withdrawal prophylaxis. These patients have excellent analgesia, but they need their previously used maintenance opioid to prevent withdrawal. Special considerations will have to be made in patients with naltrexone.Recovering patients with a history of SUD have both an intensive fear of relapsing into the active SUD as well as fear of suffering from postoperative pain. These patients require an equally effective analgesia as other patients. Depending on the type of surgery and pain intensity they need atypical opioids (eg tramadol) or strong opioids (eg buprenorphine or morphine) as a part of balanced analgesia to the same degree as other patients. Withholding effective analgesic treatment can paradoxically lead to relapses in recovering patients. The common opinion of healthcare providers to withhold strong opioids from recovering patients with SUD is obsolete. However, in order to avoid psychotropic side effects the dosages of opioids, as well as the analgesic efficacy, should be monitored closely.     

Dose-response relationship of opioids in nociceptive and neuropathic postoperative pain

The treatment of neuropathic pain with opioid analgesics is a matter of controversy among clinicians and clinician scientists. Although neuropathic pain is usually believed to be only slightly responsive to opioids, several studies show that satisfactory analgesia can be obtained if adequate doses are administered. In the present study, we tested the effectiveness of buprenorphine in 21 patients soon after thoracic surgery (nociceptive postoperative pain) and 1 month after surgery in the same 21 patients who developed postthoracotomy neuropathic pain with a burning, electrical and shooting quality. According to a double-blind randomized study, the analgesic dose (AD) of buprenorphine needed to reduce the long-term neuropathic pain by 50% (AD₅₀) was calculated and compared to the AD₅₀ in the immediate postoperative period. We found that long-term neuropathic pain could be adequately reduced by buprenorphine. However, the AD₅₀ in neuropathic pain was significantly higher relative to the AD₅₀ in the short-term postoperative pain, indicating a lower responsiveness of neuropathic pain to opioids. We also found a strict relationship between the short-term and long-term AD₅₀, characterized by a saturating effect. In fact, if the AD₅₀ soon after surgery was low, the AD₅₀ increase in the long-term neuropathic pain was threefold. By contrast, if the AD₅₀ soon after surgery was high, the AD₅₀ in neuropathic pain was only slightly increased. This suggests that, though neuropathic pain is indeed less sensitive to opioids, in some neuropathic patients a large amount of opioid resistance is already present in other painful conditions.     

Transdermal buprenorphine in pain management--experiences from clinical practice: Five case studies

Buprenorphine is a semi-synthetic opioid derived from thebaine. The transdermal formulation of buprenorphine has been available in Belgium for 3 years, during which time the Pain Clinic of the St Elisabeth of Verviers Hospital has gained experience in the use of transdermal buprenorphine for the treatment of moderate-to-severe pain. This paper presents four cases of chronic, non-malignant pain, and one case of chronic cancer pain. By starting patients on low doses and slowly titrating upwards, transdermal buprenorphine matrix patches provided effective analgesia and were well tolerated. Low doses of transdermal buprenorphine were created by cutting the smallest available matrix patch (35 mug/h) into halves or quarters. The initial dose was then gradually titrated upwards to the dose needed for optimum pain relief by the patients. No problems were encountered in switching patients from prior analgesic therapy with other opioids to transdermal buprenorphine.     

New Pain Management Options for the Surgical Patient on Methadone and Buprenorphine

Perioperative management of patients receiving opioid addiction therapy presents a unique challenge for the anesthesiologist. The goal of pain management in this patient population is to effectively manage postoperative pain, to improve patient satisfaction and outcomes, and to reduce the cost of health care. Multimodal analgesics, including nonsteroid anti-inflammatory drugs, intravenous acetaminophen, gabapentanoid agents, and low-dose ketamine infusions, have been used to improve postoperative pain and to reduce postoperative opioid use. Patients on long-term opioid management therapy with methadone and buprenorphine require special considerations. Recommendations and options for treating postoperative pain in patients on methadone and buprenorphine are outlined below. Other postoperative pain management options include patient-controlled analgesia, intravenous, and transdermal, in addition to neuraxial and regional anesthesia techniques. Special patient populations include the parturient on long-term opioid therapy. Recommendations for use of opioids in these patients during labor and delivery and in the postpartum period are discussed.     

Intravenous patient-controlled analgesia for acute postoperative pain

Intravenous patient-controlled therapy is used routinely in postoperative care in much of the developed world. Intravenous patient-controlled analgesia results in higher patient satisfaction than conventional administration of analgesics, although it appears to have no advantage over conventional analgesia in terms of adverse effects and consumption of opioids. Standard orders and nursing procedure protocols are recommended for patients receiving intravenous patient-controlled analgesia to monitor treatment efficacy and development of adverse effects. Some subgroups of patients need special consideration. For example, opioid-tolerant patients need higher postoperative opioid doses to achieve satisfactory analgesic effect. In patients with renal or hepatic insufficiency, the elimination of some opioids may be substantially impaired, and the optimal opioid should be selected based on its pharmacokinetic properties.     

Postoperative Pain Management in Spanish Hospitals: A Cohort Study Using the PAIN-OUT Registry

Pain after surgery remains a problem worldwide, although there are no published data on postoperative outcomes in Spain. We evaluated 2,922 patients on the first day after surgery in 13 tertiary care Spanish hospitals, using the PAIN-OUT questionnaire. The aims were to: assess postoperative outcomes and anesthetic/analgesic management in Orthopedics (ORT) and General Surgery (GEN) patients; explore the influence of the analgesic therapy on outcomes and opioid requirements; evaluate and compare outcomes and analgesic management according to surgical procedure. Mean worst pain and percentage of patients in severe pain were 5.6 (on a numeric rating scale of 0–10) and 39.4%, respectively, slightly lower than those reported in Western countries (range, 5.0–8.4 and 33–55%). Patients’ pain assessment (83.1%) and information were high (63.3%), but participation in decision-making (4.8) was lower than in the United States (7.0) and Europe (Germany, France, Norway, and Denmark; mean, 5.9). Patients after orthopedic surgery had the worst outcomes. General anesthesia was more frequent in GEN patients, whereas regional (central and peripheral) was more frequent in ORT surgery patients. Mean opioid consumption (20.2 mg per patient per 24 hours, oral morphine equivalents), was lower than reported and decreased >50% after regional analgesia. Intravenous morphine patient-controlled analgesia was seldom used (6.2%). Acute opioid treatments were associated with worsened outcomes whereas multimodal analgesia (mainly antipyretic analgesics–nonsteroidal anti-inflammatory drugs–opioids) were associated with improved results. Epidurals in abdominal surgery (16.7%) were also associated with better outcomes. Presurgical chronic pain (>7) and/or chronic opioid consumption, were associated with worsened pain outcomes; the latter with a 50% increase in postoperative opioid requirements. Tibia/fibula and foot surgeries (ORT), and gastric, small intestine, and anterior abdominal wall procedures (GEN) were the most painful. Rigorous control of chronic pain before surgery, and combining opioids with adjuvants and other analgesics perioperatively, might improve postoperative outcomes.

Clinical update on the pharmacology,efficacy and safety of transdermal buprenorphine

Buprenorphine was not used widely in clinical practice over many years, mainly due to analgesic potency and clinical safety concerns based on misinterpreted animal data. Contrary to previous concerns, however, no analgesic ceiling effect and no antagonism of combined pure μ‐opioid receptor agonists is seen within the therapeutic dose range. In recent studies, buprenorphine could be effectively and safely combined with full μ‐agonists, and switching between buprenorphine and another opioid provided comparable pain relief based on equianalgesic doses. Moreover, buprenorphine exerts an antihyperalgesic effect, which is due—at least in part—to antagonistic activity at κ‐opioid receptors. Buprenorphine pharmacokinetics are not altered by advanced age or renal dysfunction. In addition, the risk of respiratory depression is lower than with other opioids including morphine, hydromorphone, methadone and fentanyl. Unlike morphine and fentanyl, there is no immunosuppressive activity with buprenorphine at therapeutic analgesic doses. Transdermal buprenorphine has significantly improved the clinical use of the drug, providing continuous buprenorphine release for up to 96h. In clinical trials, patients receiving transdermal buprenorphine experienced significantly greater pain relief, better sleep, and a reduced need for rescue therapy, compared to placebo. Large‐scale post‐marketing studies have confirmed the effectiveness of transdermal buprenorphine in treating moderate‐to‐severe cancer and non‐cancer pain including neuropathic syndromes. Finally, the comparably low incidence of CNS adverse events and constipation, and the possibility of use in severe renal dysfunction without a need for dose adjustment make buprenorphine well suited for chronic pain management in at‐risk patients, such as diabetics, elderly or renally impaired individuals including those requiring haemodialysis.     

The role of methadone in cancer pain treatment – a review

Background: Methadone is an opioid analgesic of step 3 of the World Health Organization (WHO) analgesic ladder. Aim and Methods: To outline pharmacodynamics, pharmacokinetics, drug interactions, equianalgesic dose ratio with other opioids, dosing rules, adverse effects and methadone clinical studies in patients with cancer pain. A review of relevant literature on methadone use in cancer pain was conducted. Results: Methadone is used in opioid rotation and administered to patients with cancer pain not responsive to morphine or other strong opioids when intractable opioid adverse effects appear. Methadone is considered as the first strong opioid analgesic and in patients with renal impairment. Methadone possesses different pharmacodynamics and pharmacokinetics in comparison to other opioids. The advantages of methadone include multimode analgesic activity, high oral and rectal bioavailability, long lasting analgesia, lack of active metabolites, excretion mainly with faeces, low cost and a weak immunosuppressive effect. The disadvantages include long and changeable plasma half‐life, high bound to serum proteins, metabolism through P450 system, numerous drug interactions, lack of clear equianalgesic dose ratio to other opioids, QT interval prolongation, local reactions when administered subcutaneously. Conclusions: Methadone is an important opioid analgesic at step 3 of the WHO analgesic ladder. Future controlled studies may focus on establishment of methadone equianalgesic dose ratio with other opioids and its role as the first strong opioid in comparative studies with analgesia, adverse effects and quality of life taken into consideration.     

Coadministration of an Opioid Agonist and Antagonist for Pain Control

Abstract: The increased use of opioids in the treatment of chronic pain encourages the search for drugs with low abuse and tolerance potential but with potent analgesic activity. Opioid agonist‐antagonists and partial agonists have less abuse potential than do mu opioid receptor agonists such as morphine, and have been used for many years for their analgesic affects. Recently they have been approved for treatment of opioid addiction. As a guard against abuse, an opioid antagonist, such as naloxone, is added to some opioid formulations. Doctors are often hesitant to prescribe agonist‐antagonists and partial agonists to opioid‐tolerant patients, fearing that these drugs may precipitate withdrawal. Can drugs being used safely for addiction treatment also safely replace opioid agonists to provide analgesia in chronic pain patients who are opioid‐tolerant?     

The clinical use of spinal opioids,part 1

Spinal opioids are effective analgesics for surgical and non-surgical pain. Central and systemic side effects are less frequent than with epidural local anaesthetics or parenteral opioids. This review focuses on the analgesic efficacy of spinal opioids and their combination with local anaesthetics for postoperative analgesia, including patient-controlled epidural analgesia. Intrathecal administration of opioids has some advantages over their administration by the epidural route. Several factors may influence selection of the opioid; however, in most situations morphine is the drug of choice. Thoracic epidural administration of opioids seems to have no clinically important advantages over the lumbar route in terms of quality of analgesia, adverse effects, doses required or pulmonary function. However, evidence suggesting that effective postoperative analgesia can significantly improve postoperative morbidity in patients at risk is accumulating. In such patients, combined use of epidural local anaesthetics and opioids may become the technique of choice for postoperative analgesia. However, there is no evidence that this would have any clinically relevant benefit in low-risk patients.     

Postoperative pain relief in the morbidly obese patient: Feasibility study of a combined dipyrone/tramadol infusion

The aim of the prospective clinical study was to test the feasibility of a dipyrone/tramadol combination for pain therapy after laparoscopic and open obesity surgery. The study group was made up of 29 surgical patients; 14 following a median laparotomy and 15 following a laparoscopic approach. All received a continuous intravenous infusion of dipyrone (metamizol) and tramadol for pain relief.

The surgical procedure (laparotomy or laparoscopy), body mass index, postoperative analgesic requirement and pain intensity (visual analogue scale (VAS 1–10)) were documented.

Following laparotomy, the combination infusion provided effective analgesia. On the first and fourth postoperative days, the pain scores at rest were 1.5 and 2.3 respectively. The pain scores did not increase significantly with movement (2.7 and 2.2 respectively).

Following laparoscopic gastric banding the pain scores were less than 2.0 at rest and with movement on the first postoperative day. On the fourth postoperative day the pain scores at rest and with movement were 0.2.

This feasibility study suggests that a combination of the strong non-opioid dipyrone and the atypical opioid tramadol provides good analgesia following laparotomy and laparoscopic surgery for morbid obesity.     

Methadone analgesia in cancer pain patients on chronic methadone maintenance therapy

Methadone is currently best known for its use as the maintenance drug in opioid addiction. The main concern when using methadone for the treatment of pain is its long and unpredictable half-life, which is associated with the risk of delayed toxicity. This may result in side effects such as sedation and respiratory depression if careful titration and close observation of individual patient responses are not performed. For this reason, methadone is often viewed as a second line opioid, after other opioids with a more predictable dose-response have been tried. We report six patients with long-term exposure to methadone as a treatment for heroin dependency, who were also treated with methadone for cancer pain. The first five patients were at least partially refractory to the analgesic effects of opioids other than methadone. All six patients achieved analgesia without sedation or respiratory depression from aggressive upward methadone titration. Methadone analgesia can be considered early in the course of treatment of patients with chronic exposure to methadone who develop new or worsening pain requiring opioid therapy.     

Analgesic efficacy and tolerability of transdermal buprenorphine in patients with inadequately controlled chronic pain related to cancer and other disorders: a multicenter,randomized, double-blind,placebo-controlled trial

BACKGROUND: Buprenorphine is a potent opioid analgesic that is available in sublingual and parenteral formulations. A new formulation, buprenorphine transdermal delivery system (TDS), has been developed. OBJECTIVE: The aim of this study was to compare the analgesic efficacy and tolerability of the 3 available dosages of buprenorphine TDS (35.0, 52.5, and 70.0 microg/h) with placebo. METHODS: This was a randomized, double-blind, placebo-controlled, multicenter study. Patients with chronic, severe pain related to cancer or other diseases and inadequately controlled with weak opioids were randomized to receive buprenorphine TDS 35.0, 52.5, or 70.0 microg/h or placebo patch for up to 15 days. A new patch was applied every 72 hours, for a total of 5 patches. All patients were permitted rescue analgesia with sublingual buprenorphine tablets (0.2 mg) as required for breakthrough pain. RESULTS: A total of 157 patients (86 women, 71 men; mean [SD] age, 58.7 [11.8] years) were initially enrolled in the study. Buprenorphine TDS was associated with significantly higher response rates than was placebo at the 35.0- and 52.5-microg/h dosages (36.6% and 47.5%, respectively, vs 16.2%; P=0.032 and P=0.003, respectively) and a numerically higher response rate at 70.0 microg/h (33.3%), although this difference did not reach statistical significance. Patients treated with buprenorphine TDS experienced a 56.7% reduction in use of sublingual rescue analgesic during the study compared with an 8% reduction with the placebo patch. A total of 43.5% of patients treated with buprenorphine TDS reported good or complete pain relief compared with 32.4% in the placebo group. Pain intensity decreased in a dose-dependent manner with buprenorphine TDS, and the duration of sleep uninterrupted by pain was improved by the end of the study. More than three fourths (78.8%) of patients in the placebo and buprenorphine TDS groups reported at least 1 adverse event (AE) during the study. The most common AEs were central nervous system and gastrointestinal symptoms. The majority of treatment-related AEs were mild or moderate in intensity and were typical of those occurring at the beginning of therapy with a strong opioid. CONCLUSIONS: Buprenorphine TDS was shown to be an effective analgesic against chronic, severe pain in this study population. Patients treated with this new formulation of buprenorphine showed improved duration of sleep and reduced need for additional oral analgesics.     

Peripheral opioid analgesia for the treatment of neuropathic pain: Gene mutation to virus mediated gene transfer

Neuropathic pain can result from a number of different diseases, medical interventions and injuries. In addition to varying aetiologies, neuropathic pain may also differ in the anatomical location of the lesion – from peripheral nociceptors to the highest centres in the brain. The management of neuropathic pain continues to be a challenge for clinicians and despite taking prescribed medication for pain, patients with neuropathic pain continue to have pain of moderate severity. The use of opioids for the treatment of chronic neuropathic pain remains controversial. Recent studies demonstrate opioid analgesics are effective in neuropathic pain states but their use is often limited by unacceptable side effects that are mediated by opioid actions in the central nervous system. While it was once dogma that opioids exert their analgesic effects by binding to receptors in the central nervous system, there is a growing recognition of a potent peripheral analgesia in experimental models of inflammatory and neuropathic pains, and in clinical settings. The working model is that peripheral opioids can be used to treat neuropathic pain while avoiding the often dose-limiting and unacceptable central nervous system mediated side effects. Our work has focused on characterizing this peripheral opioid analgesia such that it can be exploited to develop novel and potent peripheral analgesics for the treatment of neuropathic pain. This article will set the clinical stage for the need for novel treatments for neuropathic pain, the use of gene mutation strategies to make the case for the use of opioids in treating neuropathic pain, the demonstration of peripheral opioid analgesia in neuropathic pain, and our work with virus mediated gene transfer to enhance peripheral opioid analgesia in neuropathic pain.     

The safety of concurrent administration of opioids via epidural and intravenous routes for postoperative pain in pediatric oncology patients

Supplementation of epidural opioid analgesia with intravenous opioids is usually avoided because of concern about respiratory depression. However, the choice of adjunct analgesic agents for pediatric oncology patients is limited. Antipyretic drugs may mask fever in neutropenic patients, and nonsteroidal anti-inflammatory agents may exert antiplatelet effects and interact with chemotherapeutic agents. We examined the safety of concurrent use of epidural and intravenous opioids in a consecutive series of 117 epidural infusions in pediatric patients and compared our findings to those reported by other investigators. We observed a 0.85% rate of clinically significant respiratory complications. The single adverse event was associated with an error in dosage. In our experience, the supplementation of epidural opioid analgesia with intravenous opioids has been a safe method of postoperative pain control for pediatric patients with cancer.     

Outcomes After Intravenous Opioids in Emergency Patients: A Prospective Cohort Analysis

Objectives: Pain management continues to be suboptimal in emergency departments (EDs). Several studies have documented failures in the processes of care, such as whether opioid analgesics were given. The objectives of this study were to measure the outcomes following administration of intravenous (IV) opioids and to identify clinical factors that may predict poor analgesic outcomes in these patients. Methods: In this prospective cohort study, emergency patients were enrolled if they were prescribed IV morphine or hydromorphone (the most commonly used IV opioids in the study hospital) as their initial analgesic. Patients were surveyed at the time of opioid administration and 1 to 2 hours after the initial opioid dosage. They scored their pain using a verbal 0–10 pain scale. The following binary analgesic variables were primarily used to identify patients with poor analgesic outcomes: 1) a pain score reduction of less than 50%, 2) a postanalgesic pain score of 7 or greater (using the 0–10 numeric rating scale), and 3) the development of opioid-related side effects. Logistic regression analyses were used to study the effects of demographic, clinical, and treatment covariates on the outcome variables. Results: A total of 2,414 were approached for enrollment, of whom 1,312 were ineligible (658 were identified more than 2 hours after IV opioid was administered and 341 received another analgesic before or with the IV opioid) and 369 declined to consent. A total of 691 patients with a median baseline pain score of 9 were included in the final analyses. Following treatment, 57% of the cohort failed to achieve a 50% pain score reduction, 36% had a pain score of 7 or greater, 48% wanted additional analgesics, and 23% developed opioid-related side effects. In the logistic regression analyses, the factors associated with poor analgesia (both <50% pain score reduction and postanalgesic pain score of ≥7) were the use of long-acting opioids at home, administration of additional analgesics, provider concern for drug-seeking behavior, and older age. An initial pain score of 10 was also strongly associated with a postanalgesic pain score of ≥7. African American patients who were not taking opioids at home were less likely to achieve a 50% pain score reduction than other patients, despite receiving similar initial and total equianalgesic dosages. None of the variables we assessed were significantly associated with the development of opioid-related side effects. Conclusions: Poor analgesic outcomes were common in this cohort of ED patients prescribed IV opioids. Patients taking long-acting opioids, those thought to be drug-seeking, older patients, those with an initial pain score of 10, and possibly African American patients are at especially high risk of poor analgesia following IV opioid administration.