Adjuvant Analgesics in Acute Pain - Evaluation of Efficacy.

PURPOSE OF THE REVIEW: Acute postoperative pain impacts a significant number of patients and is associated with various complications, such as a higher occurrence of chronic postsurgical pain as well as increased morbidity and mortality. RECENT FINDINGS: Opioids are often used to manage severe pain, but they come with serious adverse effects, such as sedation, respiratory depression, postoperative nausea and vomiting, and impaired bowel function. Therefore, most enhanced recovery after surgery protocols promote multimodal analgesia, which includes adjuvant analgesics, to provide optimal pain control. In this article, we aim to offer a comprehensive review of the contemporary literature on adjuvant analgesics in the management of acute pain, especially in the perioperative setting. Adjuvant analgesics have proven efficacy in treating postoperative pain and reducing need for opioids. While ketamine is an established option for opioid-dependent patients, magnesium and α2-agonists have, in addition to their analgetic effect, the potential to attenuate hemodynamic responses, which make them especially useful in painful laparoscopic procedures. Furthermore, α2-agonists and dexamethasone can extend the analgesic effect of regional anesthesia techniques. However, findings for lidocaine remain inconclusive.

[Cancer pain relief with drugs and neurolytic nerve blocks]. / A rosszindulatú daganatos fájdalom kezelése gyógyszerekkel és idegblokádokkal.

Drug therapy with non-opioid, opioid and adjuvant drugs is the mainstay of cancer pain relief. The three step analgesic ladder, published by WHO in 1986 Geneva, is useful for oncologists and general practitioners.
The first step is giving minor analgesics and adjuvant drugs; the second is giving minor analgesics, weak opioid and adjuvant drugs; the third step is giving minor analgesics, strong opioids and adjuvant drugs. For those patients who have severe pain it is a waste of time to prescribe the drugs of the first and second step, we suggest to start immediately with strong opioids!
Analgetic drugs should be given by the clock: the next dose is given before the effect of previous one has fully worn off. In this way it is possible to relieve pain continuously.
In selected cases the analgetic effect of nerve blockade is much better than that of the drug treatment. With successful blockades the patient can stop taking analgetic drugs for a long period of time and the blockades can be performed repeatedly. We briefly summarise the three most effective neuroblockades.

Adjuvant use of melatonin for pain management in dysmenorrhea - a randomized double-blinded, placebo-controlled trial.

PURPOSE: Dysmenorrhea is a common, recurring, painful condition with a global prevalence of 71%. The treatment regime for dysmenorrhea includes hormonal therapies and NSAID, both of which are associated with side effects. A dose of 10 mg melatonin daily has previously been shown to reduce the level of pelvic pain in women with endometriosis. We chose to investigate how this regime, administered during the week of menstruation, would affect women with dysmenorrhea but without any signs of endometriosis, as adjuvant analgesic treatment. METHODS: Forty participants with severe dysmenorrhea were randomized to either melatonin or placebo, 20 in each group. Our primary outcome was pain measured with numeric rating scale (NRS); a difference of at least 1.3 units between the groups was considered clinically significant. Secondary outcomes were use of analgesics, as well as absenteeism and amount of bleeding. Mixed model was used for statistical analysis. RESULTS: Eighteen participants completed the study in the placebo group and 19 in the melatonin group. Mean NRS in the placebo group was 2.45 and 3.18 in the melatonin group, which proved to be statistically, although not clinically significant. CONCLUSION: This randomized, double-blinded, placebo-controlled trial could not show that 10 mg of melatonin given orally at bedtime during the menstrual week had better analgesic effect on dysmenorrhea as compared with placebo. However, no adverse effects were observed. CLINICAL TRIALS: NCT03782740 registered on 17 December 2018.

The current clinical use of adjuvant analgesics for refractory cancer pain in Japan: a nationwide cross-sectional survey.

BACKGROUND: Although adjuvant analgesics are used to treat opioid-refractory cancer pain, there is insufficient evidence to support this practice and limited data to guide the choice depending on cancer pain pathophysiology, dose titration and starting dose. This survey aimed to clarify the current use of adjuvant analgesics for treating opioid-refractory cancer pain. METHODS: In this cross-sectional study, we sent an online survey questionnaire to 208 certified palliative care specialists. Primary outcomes were (i) effective pathophysiological mechanism of cancer pain and (ii) initiating doses and time period to the first response to each adjuvant analgesic therapy. RESULTS: In total, 87 (42%) palliative care specialists responded. Of all patients with cancer pain, 40% of patients (median) with refractory cancer pain were prescribed adjuvant analgesics. Additionally, 94.3, 93.1 and 86.2% of palliative care specialists found dexamethasone/betamethasone effective for neuropathic pain caused by tumor-related spinal cord compression, pregabalin effective for malignant painful radiculopathy and dexamethasone/betamethasone effective for brain tumor or leptomeningeal metastases-related headache, respectively. The median starting dose of pregabalin, dexamethasone/betamethasone, lidocaine and ketamine were 75, 4, 200, and 50 mg/day, respectively, and the median time to the first response of those medications were 5, 3, 2 and 3 days, respectively. CONCLUSIONS: Many palliative care specialists select adjuvant analgesics depending on the pathophysiological mechanism of cancer pain in each case. They used such adjuvant analgesics in low doses for cancer pain with short first-response periods.

Attitude of Japanese palliative care specialists towards adjuvant analgesics cancer-related neuropathic pain refractory to opioid therapy: a nationwide cross-sectional survey.

Cancer-related neuropathic pain (CNP) requires therapy involving multiple pharmaceuticals, including anticonvulsants and antidepressants; however, strong evidence to support this practice is limited. This study is a cross-sectional questionnaire-based survey. As the standard dose of adjuvant analgesics for CNP refractory to opioid therapy is not clear, the purpose of this study is to clarify the opinions of specialists about the usage of duloxetine and pregabalin for patients with CNP refractory to opioid therapy. Two hundred and eight certified palliative care specialists were surveyed and a total of 87 (42%) responses were analyzed. Twenty-five percent of specialists had considered increasing duloxetine doses up to 60 mg/day and 58% had considered increasing pregabalin doses up to 300 mg/day for CNP refractory to opioid therapy. However, 23% of the specialists succeeded in increasing duloxetine doses up to 60 mg/day and 17% in increasing pregabalin doses up to 300 mg/day, respectively.

Pharmacological Treatment of Pain in Cancer Patients: The Role of Adjuvant Analgesics, a Systematic Review.

CONTEXT: In patients with cancer, pain is one of the most feared and burdensome symptoms. Adjuvant analgesics are an important cornerstone on which treatment of pain in patients with cancer is based. OBJECTIVES: To update our guidelines for the treatment of pain in patients with cancer, we performed a systematic review on the use of adjuvant analgesics in pain in cancer. METHODS: A systematic search of the literature was performed searching for articles that studied the effect of (1) antidepressants, (2) anti-epileptics, (3) N-methyl-d-aspartate (NMDA) receptor antagonists, and (4) other adjuvant analgesics in patients with cancer pain and described their effects on pain intensity and/or side effects. RESULTS: Based on the keywords and after reading the full papers, we could include 12 papers on anticonvulsants, 10 papers on antidepressants, four on NMDA receptor antagonists, and 10 papers on other adjuvant analgesics. The methodological quality of the included papers was graded as low to very low. Overall, there was a low quality of evidence that gabapentin, pregabalin, amitriptyline, and venlafaxine were effective in reducing pain intensity in patients with cancer pain. There was insufficient evidence on the effectiveness of lamotrigine, levetiracetam, NMDA antagonists, cannabinoids, corticosteroids, and local anesthetics on reducing pain intensity in patients with cancer pain. CONCLUSION: The quality of currently available evidence on the effectiveness of adjuvant analgesics in the treatment of cancer pain is low. The treatment of pain associated with cancer should be tailored to the patient's personal preferences.

Advances in the Management of Acute Postsurgical Pain: A Review.

Despite the millions of surgeries performed every year around the world, postoperative pain remains prevalent and is often addressed with inadequate or suboptimal treatments. Chronic postsurgical pain is surprisingly prevalent, and its rate varies with the type of surgery, as well as with certain patient characteristics. Thus, better clinical training is needed as well as patient education. As pain can be caused by more than one mechanism, multimodal or balanced postsurgical analgesia is appropriate. Pharmacological agents such as opioid and nonopioid pain relievers, as well as adjuvants and nonpharmacologic approaches, can be combined to provide better and opioid-sparing pain relief. Many specialty societies have guidelines for postoperative pain management that emphasize multimodal postoperative analgesia. These guidelines are particularly helpful when dealing with special populations such as pregnant patients or infants and children. Pediatric pain control, in particular, can be challenging as patients may be unable to communicate their pain levels. A variety of validated assessment tools are available for diagnosis. Related to therapy, most guidelines agree on the fact that codeine should be used with extreme caution in pediatric patients as some may be "rapid metabolizers" and its use may be life-threatening. Prehabilitation is a preoperative approach that prepares patients in advance of elective surgery with conditioning exercises and other interventions to optimize their health. Prehabilitation may have aerobic, strength-training, nutritional, and counseling components. Logistical considerations and degree of patient adherence represent barriers to effective prehabilitation programs. Notwithstanding all this, acute postoperative pain represents a clinical challenge that has not yet been well addressed.

Glucocorticoid Effect in Cancer Patients.

The use of glucocorticoids is very varied in the context of cancer patients and includes the treatment of symptoms related to cancer, but also the management of the most common side effects of antitumor treatments or adverse events related to the immune system. There is a quantity of experimental evidence demonstrating that cancer cells are immunogenic. However, the effective activation of anticancer T cell responses closely depends on an efficient antigen presentation carried out by professional antigen-presenting cells such as dendritic cells (DCs). The classic strategies to improve the medical management of inflammation are aimed at exacerbating the host's immune response. Although successful in treating a number of diseases, these drugs have limited efficacy and variable responses can lead to unpredictable results. The ideal therapy should reduce inflammation without inducing immunosuppression and remains a challenge for healthcare personnel.

A Practical Approach to Using Adjuvant Analgesics in Older Adults.

The adjuvant analgesics are a large and diverse group of drugs that were developed for primary indications other than pain and are potentially useful analgesics for one or more painful conditions. The "adjuvant" designation reflects their early use as opioid co-analgesics for cancer pain. During the past 3 decades, their role in pain management has changed with the advent of many new entities, emerging data from numerous analgesic trials, and growing clinical experience. Many of these drugs are now used as primary analgesics for specific types of chronic pain. With proper patient selection and cautious administration, they can potentially contribute meaningfully to the management of chronic pain in older adults. A practical approach categorizes the many adjuvant analgesics by broad indications: multipurpose drugs and drugs that target neuropathic pain, musculoskeletal pain, and cancer pain, respectively. This article reviews the status of the evidence supporting the analgesic potential of the adjuvant analgesics and discusses best practices in terms of drug selection and dosing. J Am Geriatr Soc 68:691-698, 2020.

Nonsteroidal Antiinflammatory Drugs for Acute and Chronic Pain.

Understanding nonsteroidal antiinflammatory drug (NSAID) use and impact on common rheumatic and arthritic conditions is critical to reconciling their appropriate use with their potentially serious adverse effects. NSAIDs have a profound impact on the treatment of connective tissue disorders because of their ability to address the underlying cause with specific benefits of decreasing stiffness and inflammation, and improving mobility. NSAID use is twice as common as opioid use, and inappropriate use of NSAIDs is widespread. NSAID use should be monitored and the impact understood to mitigate the risks. NSAID discontinuation should be evidence based and individualized to specific requirements.

Assessment and Management of Chronic Pain in the Seriously Ill.

The intent of this article is to help clinicians to have practical knowledge and skills related to both assessment and pharmacotherapy of chronic pain in the seriously ill patients. Treating patients with chronic pain and progressive disease should include assessment of "total pain" (physical, psychological, and spiritual suffering) and the care givers as part of treatment team. Effective management of chronic pain starts with thorough assessment and diagnosis of the pain syndrome. A worldwide consensus endorses use of multimodal approach and opioid pharmacotherapy as the mainstay approach to moderate to severe pain in cancer and pain associated with serious illness.

Trends in prior receipt of prescription opioid or adjuvant analgesics among patients with incident opioid use disorder or opioid-related overdose from 2006 to 2016.

BACKGROUND: With increasing efforts to scrutinize and reduce opioid prescribing, limited data exist on the recent trend in receipt of prescription pain medications before diagnosis of opioid use disorder (OUD) or opioid-related overdose (OD). METHODS: Using 2005-2016 Truven MarketScan Commercial Claims databases, we assessed trends in annual 1) incidence of OUD or OD and 2) prevalence of receipt of prescription opioids or four commonly-prescribed adjuvant analgesics among patients newly diagnosed with OUD/OD. Trends were examined in the overall sample and by 3 age groups, including youths (≤18 years), adults (19-64 years), and older adults (≥65 years). RESULTS: The incidence of diagnosed OUD or OD increased more than 3-fold from 4.99 to 23.81 per 10,000 persons from 2006 to 2016, with the highest increase (14.18-fold) seen in older adults, followed by adults (3.53-fold), and youths (0.16-fold). Between 2006 and 2016, the proportion of patients with incident OUD/OD who received anticonvulsant adjuvant analgesics in the year before diagnosis increased (from 23.4% to 34.3% [P-trend = .005]) whereas the proportion receiving high-dose prescriptions opioids decreased (from 45.5% to 34.8% [P-trend =< .001]). A decreasing trend was observed in general for tricyclic antidepressants and serotonin and norepinephrine reuptake inhibitors. DISCUSSION: In US commercially insured patients newly diagnosed with OUD/OD, receipt of high-dose opioid prescriptions preceding the diagnosis decreased over time, paralleled by increased use of anticonvulsants commonly prescribed for pain conditions. Further investigations are warranted to understand how prescribed and anticonvulsants contribute to the development of OUD/OD.

Opioid responsiveness of nociceptive versus mixed pain in clinical cancer patients.

OBJECTIVE: To investigate whether clinical cancer patients with mixed nociceptive-neuropathic pain are less responsive to opioids than patients with nociceptive pain. BACKGROUND: Pain is common in advanced cancer patients. Pain driven by neuropathic mechanisms is considered to be resistant to opioids. This hypothesis is mainly based on animal studies and single-dose opioid studies in humans but has not been confirmed in clinical practice. METHODS: Data were prospectively collected from 240 clinical cancer pain patients using opioids. Multiple linear regression was used for assessing the associations between the logarithm of the morphine equivalent dose (MED) at three days after admission (T = 3d) relative to admission (T = 0d) (logRMED) and type of pain (nociceptive versus mixed pain), corrected for gender, age, primary cancer site and use of non-opioid and adjuvant analgesics. As secondary outcome measures, associations between logMED and logPFent (fentanyl plasma level) at T = 3d and type of pain were assessed. RESULTS: Pain intensity between T = 0d and T = 3d was significantly and evenly reduced in patients with nociceptive pain (n = 173) and mixed pain (n = 67). Median (interquartile range) MED was 20 (10-52) and 20 (20-80) mg (T = 0d), 40 (10-67) and 40 (20-100) mg (T = 3d), median PFent (T = 3d) was 1.59 (0.58-3.19) and 1.38 (0.54-4.39) ng/ml, none of them significantly different, in patients with nociceptive and mixed pain, respectively. Neither logRMED, logMED (T = 3d), or logPFent (T = 3d) was significantly associated with type of pain, after correction for confounding factors. CONCLUSIONS: We conclude that, at least in clinical cancer patients, mixed pain is as responsive to opioids as nociceptive pain.

Treatment of patients with neuropathic pain and provision of drug information by clinical pharmacists

Abstract Patient's satisfaction with healthcare services has an influence on pain management, which can be improved by patient education. Therefore, this study was aimed at identifying primary care health service opportunities in the treatment of neuropathic pain and assessing patients' satisfaction with the provision of drug information by clinical pharmacists. This was a cross- sectional, prospective study conducted at a pain unit during March-May 2017. Patients aged >18 years; diagnosed with neuropathic pain; and who used amitriptyline, gabapentin, pregabalin, or duloxetine were included. They were verbally informed about drug treatment by a clinical pharmacist, and their satisfaction was evaluated after 1 month. In all, 90 patients were included. The median duration for which the patients experienced pain until hospital admission was 3.6 years; furthermore, this duration was longer among women (p < 0.05). However, the median time to seeking advice from doctors was 3 months. The patients (15.6%) were less likely to admit pain unit initially and 46.7% had visited different units before being admitted to a pain unit. More than 95% of the patients indicated that they had received information from a pharmacist at a clinic and were satisfied with the provision of information (median duration, 8.5 min). Thus, the involvement of pharmacists in multidisciplinary pain management may help improve health- related outcomes at hospitals and/or in community care settings

Perioperative analgesia: ever-changing technology and pharmacology.

Our understanding of pain and its long-term implications have dramatically changed with the advent of advancements in molecular mechanisms involved in acute or postoperative pain and chronic pain. This better understanding has led to multiple pharmacologic advancements to better treat pain with minimal side effects. Currently, we are still struggling to find the right balance between all of the different modalities that we have at our leisure. In order to best take care of postoperative pain, we are improving patient satisfaction, decreasing hospital stays, and decreasing the development of long-term pain and its related complications. However, despite using a multimodal approach that includes newer technologies, we still have a long way to go before we can guarantee a pain-free postoperative course or a comfortable end for a terminally ill patient. These arms of anesthesiology are ever changing. Anesthesiologists have taken a leadership role in perioperative pain management and clinical research designed for the improvement of pain.

Pharmacological pain management in chronic pancreatitis.

Intense abdominal pain is a prominent feature of chronic pancreatitis and its treatment remains a major clinical challenge. Basic studies of pancreatic nerves and experimental human pain research have provided evidence that pain processing is abnormal in these patients and in many cases resembles that seen in neuropathic and chronic pain disorders. An important ultimate outcome of such aberrant pain processing is that once the disease has advanced and the pathophysiological processes are firmly established, the generation of pain can become self-perpetuating and independent of the initial peripheral nociceptive drive. Consequently, the management of pain by traditional methods based on nociceptive deafferentation (e.g., surgery and visceral nerve blockade) becomes difficult and often ineffective. This novel and improved understanding of pain aetiology requires a paradigm shift in pain management of chronic pancreatitis. Modern mechanism based pain treatments taking into account altered pain processing are likely to increasingly replace invasive therapies targeting the nociceptive source, which should be reserved for special and carefully selected cases. In this review, we offer an overview of the current available pharmacological options for pain management in chronic pancreatitis. In addition, future options for pain management are discussed with special emphasis on personalized pain medicine and multidisciplinarity.

A two-case report of successful treatment with pregabalin for refractory chemotherapy-induced hiccups

<b>Purpose</b>: Hiccups are a symptom that often appear in lung cancer patients during medical treatment. Although various drugs and non-pharmacologic therapies are used to treat them, they often are not effective. We report 2 cases of successful treatment for refractory hiccups due to chemotherapy for lung cancer using pregabalin. <b>Case report</b>: Both patients had advanced squamous lung cancer. That in case 1 was treated using chemotherapy with carboplatin and paclitaxel, while the case 2 received nedaplatin and irinotecan. Hiccups occurred and became exacerbated during chemotherapy in both, and were considered to be induced by the anticancer drugs. Separate treatments with metoclopramide, chlorpromazine, and gabapentin did not have any effect, whereas immediate improvement was seen after taking pregabalin in both cases. <b>Conclusion</b>: Pregabalin, often used as an adjuvant analgesic, controls excessive neuronal excitement. In the present cases, effective relief of refractory hiccups was seen.

Effectiveness and long term safety of gabapentin in the management of neuropathic pain of terminally-ill cancer patients

<b>Purpose</b>: This study is aimed at the evaluation of the effectiveness and safety of gabapentin for the management of cancer-related neuropathic pain in terminally-ill cancer patients. <b>Methods</b>: We investigated terminally-ill cancer patients prescribed gabapentin for the management of cancer-related neuropathic pain, from November 200X to October 200X+2. We assessed average daily pain on the numerical rating scale (NRS) before administration, after one week, and while on a stable dose. <b>Result</b>: 44 patients were enrolled during this period and 19 patients completed the study. The medication and the survival period on average were 52.0 and 67.2 days, respectively. The average gabapentin daily dose after one week was 358 mg. The average period needed to reach a stable dose was 11.6 days and the average stable daily dose was 463 mg (male 620 mg, female 289 mg). The mean NRS decreased from 5.7 (before) to 2.1 (after one week, <I>p</I><0.001) and 1.9 (stable dose, <I>p</I><0.001), respectively. 57.9% of patients showed side effects, somnolence in 52.6%, delirium in 5.3%, tremor in 5.3%. <b>Conclusion</b>: Gabapentin can be expected to be effective and safe for managing cancer-related neuropathic pain for a long period even when in critical condition through careful titration. Palliat Care Res 2011; 6(1): 101-108

Current pharmacological management of chronic pain

Chronic pain is associated with disabling physical and emotional symptoms. Patients with chronic pain utilize more health services, have an impaired sense of well-being and frequently experience anxiety or depression. Unfortunately, treatment for chronic pain is not always correctly targeted, which leads to a reduced quality of life. Treatment of chronic pain involves a comprehensive approach using medication and functional rehabilitation. The usual approach for mild to moderate pain is to start with nonopioid analgesics. Also, trying antidepressant drugs for sleep loss and gabapentin for neuropathic pain or fibromyalgia is appropriate. For moderate to severe chronic pain, opioid analgesics can be used without any serious side effects if adequately used at the right dosage. It is important to provide guidance on the safe use of analgesics and other psychoactive drugs. Dosing of acetaminophen should be limited to avoid liver toxicity, and topical analgesics are preferred for focal pain. Full-dose nonsteroidal anti-inflammatory drugs should not be used for more than short periods, in order to avoid gastrointestinal, renal, and cardiovascular complications. Mechanisms of analgesia, drug selection, and recommendations for clinical usage for the management of chronic pain are reviewed in this paper.

Successful elimination of intractable lower limb neuropathic pain by pelvic tumor invasion using ultrasound-guided sciatic nerve block

We report a case whose left lower limb neuropathic pain accompanied by pelvic tumor invasion was remarkably eliminated by ultrasound-guided sciatic nerve block. <b>Case report</b>: The subject was a sixty year old male. Pharmacological therapy was given according to the WHO analgesic ladder, but his left lower limb pain failed to respond to drugs. His intractable lower limb neuropathic pain was alleviated by ultrasound-guided sciatic nerve block. Drug delivery can be achieved with a percutaneous catheter and a disposable infusion pump. Infusions were run at 5mlh<SUP>-1</SUP> with 0.1% ropivacaine. <b>Conclusion</b>: Neuropahic pain is sometimes hard to be controlled only by opioids or adjuvant analgesics, but there is a possibility of providing pain relief by combination use with nerve blocks. Interventional techniques can be highly effective but also have the potentiality to produce significant adverse effects. Many patients have factors which would be considered a near absolute contra-indication to the use of nerve blocks such as immuno-compromise or impairment of coagulation. Skillful application of peripheral neural blockade with ultrasound imaging broadens the options for providing optimal pain management. Palliat Care Res 2011; 6(1): 313-315