Opioid analgesic dose and route conversion ratio studies: a scoping review to inform an eDelphi guideline.

BACKGROUND: Clinicians regularly prescribe opioids to manage acute and chronic cancer pain, frequently to address acute postoperative pain, and occasionally to manage chronic non-cancer pain. Clinical efficacy may be suboptimal in some patients due to side effects and/or poor response, and opioid rotation/switching (conversions) is frequently necessary. Despite the widespread practice, opioid conversion ratios are inconsistent between clinicians, practices, and countries. Therefore, we performed a scoping systematic review of opioid conversion studies to inform an international eDelphi guideline. METHODS: To ensure a comprehensive review, we conducted a systematic search across multiple databases (OVID Medline, PsycINFO, Embase, EBM-Cochrane Database of Systematic Reviews and Registered Trials, LILACS, IMEMR, AIM, WPRIM) using studies published up to June 2022. Additionally, we performed hand and Google Scholar searches to verify the completeness of our findings. Our inclusion criteria encompassed randomized and non-randomized studies with no age limit, with only a few pediatric studies identified. We included studies on cancer, non-cancer, acute, and chronic pain. The level and grade of evidence were determined based on the Multinational Supportive Care in Cancer (MASCC) criteria. RESULTS: Our search yielded 21,118 abstracts, including 140 randomized (RCT) and 68 non-randomized (NRCT) clinical trials. We compared these results with recently published conversion ratios. Modest correlations were noted between published reviews and the present scoping systematic review. CONCLUSION: The present scoping systematic review found low-quality evidence to support an opioid conversion guideline. We will use these data, including conversion ratios and type and route of administration, to inform an eDelphi guideline.

When does early palliative care influence aggressive care at the end of life?

BACKGROUND: Early palliative care improves patient quality of life and influences cancer care. The time frame of early has not been established. Eight quality measures reflect aggressive care at the end of life. We retrospectively reviewed patients who died with cancer between January 1, 2018, through December 31, 2019, and compared the timing of palliative care consultation, advance directives (AD), and home palliative care with aggressive care at the end of life (ACEOL). METHODS: Patients without ACEOL indicators were compared to patients with one or more than one indicator of ACEOL. The proportion of patients who received palliative care, completed AD, and the timing of palliative care and AD (less than 30 days, 30-90 days, and greater than 90 days prior to death) was compared for patients who had ACEOL versus those who did not. Chi-square analysis was used for categorical data, one-way ANOVA for continuous variables, and odds ratio (OR) with confidence intervals (CI) was reported as a measure of effect size. A p value ≤ 0.05 was considered significant. RESULTS: 1727 patients died, 46% were female, and the mean age was 69 (SD 11.91). Seventy-one percent had a palliative care consult, 26% completed AD, and 888 (51.4%) had at least one indicator of ACEOL. The most common indicator of ACEOL was new chemotherapy within 30 days of death, in 571 of 888 (64%) of patients experiencing ACEOL. ADs completed at any time reduced ACEOL (OR 0.80, 95%CI 0.64-0.99). Palliative care initiated at 30 days was associated with a greater risk of ACEOL (OR 5.32, 95% CI 3.94-7.18) and initiated between 30 and 90 days (OR 1.39, 95% CI 1.07-1.80) compared to no palliative care but was associated with reduced chemotherapy as an indicator of ACEOL when > 90 days (OR 0.46, 95% CI 0.38-0.57) before death. DISCUSSION: Completed ADs were associated with reduced chemotherapy in the last 30 days of life and reduced ICU admissions. This may reflect goals of care and end-of-life discussions and transition of care to comfort measures. Palliative care paradoxically when initiated within 90 days before death was associated with greater ACEOL compared to no palliative care. This may be due to consultation late in the course of illness with a focus on crisis management in patients frequently utilizing the health care system. There is an associated reduction in the use of chemotherapy in the last 30 days of life if palliative care is consulted 90 days prior to death. CONCLUSIONS: An initial palliative care consult greater than 90 days before death and ADs completed at any time during the disease trajectory was associated only with reduced chemotherapy in the last 30 days of life compared with no palliative care among the 7 ACEOL indicators. ADs were associated with reduced ICU admissions. Most palliative care consults occurred within 90 days of death and a palliative care consult within 90 days of death is not an optimal utilization of services.

The Management of Nausea and Vomiting Not Related to Anticancer Therapy in Patients with Cancer.

OPINION STATEMENT: In cancer patients, the management of nausea and vomiting that is not directly related to treatment is challenging. Much current practice is based on expert opinion and anecdote. Fortunately, over recent years, a number of quality trials have been undertaken to strengthen the evidence base that guides the care of our patients with these distressing symptoms. Much is still unknown however. In this article, we present the latest literature that addresses some of the outstanding issues.

Treating Chronic Pain with Buprenorphine-The Practical Guide.

OPINION STATEMENT: Buprenorphine has unique and favorable pharmacological properties that make it useful in a variety of clinical scenarios. It has been recommended to consider buprenorphine first-line opioid for chronic pain, especially in the elderly as it may be associated with less cognitive impairment, falls, sexual dysfunction, and sarcopenia when compared with schedule II opioids. It may be useful in patients with comorbid substance use disorder or non-medical opioid use, as there is less risk of misuse, euphoria and it may improve mood. When used to treat opioid use disorder, the training and waiver was recently waived for licensed practitioners with a DEA and any provider may prescribe buprenorphine. For many reasons outlined in this article, the popularity of using buprenorphine for analgesia continues to grow and a practitioner should consider this as an excellent and safe option for chronic pain.

Pain or fatigue: which correlates more with suffering in hospitalized cancer patients?

BACKGROUND: The association of pain and suffering seems intuitive, but evidence substantiating this association is lacking. In studies of cancer patients, fatigue, rather than pain, is the most prevalent and debilitating symptom. This study aimed to compare the correlation of pain and fatigue to suffering, and identify other potential sources of suffering in cancer patients treated in a palliative care unit. METHODS: One hundred fifty cancer patients were surveyed. Fifteen variables were measured on a 0- to 10-point scale: suffering, pain, level of acceptable pain, effect of pain on quality of life, fatigue, level of acceptable fatigue, effect of fatigue on quality of life, and specific types of suffering. Univariable associations with suffering were made with Pearson correlation (continuous variables) or t test (binary predictors). Multivariable associations with suffering were assessed with linear regression analysis and bootstrapping. RESULTS: In multivariable analysis, highest pain (parameter estimate 0.38) had a greater impact on suffering than highest fatigue (parameter estimate 0.21). When other variables were assessed, 38% of the variability in suffering was accounted for by pain "now", fatigue in the past 24 hours, and age. CONCLUSION: The most important predictors of greater suffering in hospitalized cancer patients are pain, younger age, and fatigue. Despite their significant effect on suffering, other underlying contributors to suffering have yet to be identified. Designing interventions to reduce fatigue, in addition to pain management, may help in alleviating overall suffering.

The Benefits of Olanzapine in Palliating Symptoms.

OPINION STATEMENT: Olanzapine has become a major drug in the management of chemotherapy-induced nausea and vomiting as a prophylactic agent. In addition, a recent randomized trial has demonstrated its benefits in treating nausea and vomiting associated with advanced cancer. The added benefit to olanzapine is that it also stimulates appetite. As a result, since it treats multiple symptoms associated with advanced cancer, it is likely to become the antiemetic of choice in palliative care at least in the USA. The added benefit of treating insomnia and the avoidance of benzodiazepines should place olanzapine in at the top of the list of drugs to use for patients who do complain of insomnia. There is no good evidence that it potentiates the respiratory depression of opioids unlike benzodiazepines. The evidence is weak that olanzapine in as an adjuvant analgesic. Hopefully, future trials will explore this in greater depth. The benefits of adding olanzapine to potent opioids are that it may reduce craving, drug cues, and opioid misuse. Other symptoms like anxiety and depression may be addressed by the addition of olanzapine to standard antidepressants.

EEG Correlates of Central Origin of Cancer-Related Fatigue.

The neurophysiological mechanism of cancer-related fatigue (CRF) remains poorly understood. EEG was examined during a sustained submaximal contraction (SC) task to further understand our prior research findings of greater central contribution to early fatigue during SC in CRF. Advanced cancer patients and matched healthy controls performed an elbow flexor SC until task failure while undergoing neuromuscular testing and EEG recording. EEG power changes over left and right sensorimotor cortices were analyzed and correlated with brief fatigue inventory (BFI) score and evoked muscle force, a measure of central fatigue. Brain electrical activity changes during the SC differed in CRF from healthy subjects mainly in the theta (4-8 Hz) and beta (12-30 Hz) bands in the contralateral (to the fatigued limb) hemisphere; changes were correlated with the evoked force. Also, the gamma band (30-50 Hz) power decrease during the SC did not return to baseline after 2 min of rest in CRF, an effect correlated with BFI score. In conclusion, altered brain electrical activity during a fatigue task in patients is associated with central fatigue during SC or fatigue symptoms, suggesting its potential contribution to CRF during motor performance. This information should guide the development and use of rehabilitative interventions that target the central nervous system to maximize function recovery.

Checkpoint Inhibitors, Palliative Care, or Hospice.

PURPOSE: Checkpoint (CTLA-4, PD-1, and PD-L1) inhibitors have changed the face of oncology. A subset of patients enjoys long, gratifying treatment responses. Unfortunately, most patients do not respond even when expressing favorably markers such as PD-L1. Checkpoint inhibitors are largely palliative (though a subset have long-term cancer responses) and as such patient-related outcome measures should be included when evaluating benefits. The purpose of this review is to place checkpoint inhibitor trials within a palliation context. Included is a discussion on potential adverse effects on end-of-life care. RECENT FINDINGS: Pivotal studies have presented efficacy and safety data but we have little published data on quality of life or symptom responses. Extension of life is approximately 2-3 months with some long-term responses in a minority of patients. The cost of checkpoint inhibitors is high for utility (as measured by quality-adjusted life-year saved) and ranges from 81,000 to over 200,000 USD for quality-adjusted life-year saved. Adverse effects were suboptimally reported in multiple studies. Meaningful responses in many trials as defined by the European Society of Medical Oncology are modest. Because at least for now, checkpoint inhibitors are used in advanced cancer and largely palliative patients should be seen by palliative specialists, symptoms related to cancer assessed, and advanced directives addressed. Treatment-related autoimmune diseases represent toxicities which oncologists and palliative specialists must understand. This means that palliative care specialists should know about the benefits and adverse effects of these agents. Whether checkpoint inhibitors increase or decrease aggressive care, hospice referrals, and costs at the end of life is yet to be determined.

Cannabinoids for Symptom Management and Cancer Therapy: The Evidence.

Cannabinoids bind not only to classical receptors (CB1 and CB2) but also to certain orphan receptors (GPR55 and GPR119), ion channels (transient receptor potential vanilloid), and peroxisome proliferator-activated receptors. Cannabinoids are known to modulate a multitude of monoamine receptors. Structurally, there are 3 groups of cannabinoids. Multiple studies, most of which are of moderate to low quality, demonstrate that tetrahydrocannabinol (THC) and oromucosal cannabinoid combinations of THC and cannabidiol (CBD) modestly reduce cancer pain. Dronabinol and nabilone are better antiemetics for chemotherapy-induced nausea and vomiting (CINV) than certain neuroleptics, but are not better than serotonin receptor antagonists in reducing delayed emesis, and cannabinoids have largely been superseded by neurokinin-1 receptor antagonists and olanzapine; both cannabinoids have been recommended for breakthrough nausea and vomiting among other antiemetics. Dronabinol is ineffective in ameliorating cancer anorexia but does improve associated cancer-related dysgeusia. Multiple cancers express cannabinoid receptors directly related to the degree of anaplasia and grade of tumor. Preclinical in vitro and in vivo studies suggest that cannabinoids may have anticancer activity. Paradoxically, cannabinoid receptor antagonists also have antitumor activity. There are few randomized smoked or vaporized cannabis trials in cancer on which to judge the benefits of these forms of cannabinoids on symptoms and the clinical course of cancer. Smoked cannabis has been found to contain Aspergillosis. Immunosuppressed patients should be advised of the risks of using "medical marijuana" in this regard.

Opioids and Chronic Pain: Where Is the Balance?

Chronic opioid therapy (defined as greater than 3 months on opioids) is a common practice for those with non-cancer pain, cancer survivors with treatment-related pain, and individuals with cancer undergoing disease-modifying therapy with a survival that can be for a year or more. Recent studies have found unique long-term toxicities with opioids which reduce the utility of opioid therapy in chronic pain. The risk of addiction, depression, central hypogonadism, sleep-disordered breathing, impaired wound healing, infections, cognitive impairment, falls, non-vertebral fractures, and mortality are increased in populations on long-term opioids. Factors associated with these risks are related to dose, duration of opioid therapy, type of opioid, and formula (long-acting, short-acting). This state-of-the-art review discusses the risks and benefits of chronic opioid therapy and strategies to increase utility and diminish risks to opioid therapy.

Sunitinib-associated hypertension and neutropenia as efficacy biomarkers in metastatic renal cell carcinoma patients.

BACKGROUND: Metastatic renal cell carcinoma (mRCC) prognostic models may be improved by incorporating treatment-induced toxicities. METHODS: In sunitinib-treated mRCC patients (N=770), baseline prognostic factors and treatment-induced toxicities (hypertension (systolic blood pressure ⩾140 mm Hg), neutropenia (grade ⩾2), thrombocytopenia (grade ⩾2), hand-foot syndrome (grade >0), and asthenia/fatigue (grade >0)) were analysed in multivariate analyses of progression-free survival (PFS) and overall survival (OS) end points. RESULTS: On-treatment neutropenia and hypertension were associated with longer PFS (P=0.0276 and P<0.0001, respectively) and OS (P=0.0014 and P<0.0001, respectively), independent of baseline prognostic factors, including International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. By 12-week landmark analysis, neutropenia was significantly associated with longer PFS and OS (P=0.013 and P=0.0122, respectively) and hypertension or hand-foot syndrome with longer OS (P=0.0036 and P=0.0218, respectively). The concordance index was 0.65 (95% CI: 0.63-0.67) for IMDC classification alone and 0.72 (95% CI: 0.70-0.74) when combined with hypertension and neutropenia. Considering hypertension and neutropenia (developing both vs neither) changed IMDC-predicted median OS in each IMDC risk group (favourable: 45.3 vs 19.5 months; intermediate: 32.5 vs 8.0 months; poor: 21.1 vs 4.8 months). CONCLUSIONS: On-treatment neutropenia and hypertension are independent biomarkers of sunitinib efficacy and may add prognostic accuracy to the IMDC model.

Integration of oncology and palliative care: a systematic review.

BACKGROUND: Both the American Society of Clinical Oncology and the European Society for Medical Oncology strongly endorse integrating oncology and palliative care (PC); however, a global consensus on what constitutes integration is currently lacking. To better understand what integration entails, we conducted a systematic review to identify articles addressing the clinical, educational, research, and administrative indicators of integration. MATERIALS AND METHODS: We searched Ovid MEDLINE and Ovid EMBase between 1948 and 2013. Two researchers independently reviewed each citation for inclusion and extracted the indicators related to integration. The inter-rater agreement was high (κ = 0.96, p < .001). RESULTS: Of the 431 publications in our initial search, 101 were included. A majority were review articles (58%) published in oncology journals (59%) and in or after 2010 (64%, p < .001). A total of 55 articles (54%), 33 articles (32%), 24 articles (24%), and 14 articles (14%) discussed the role of outpatient clinics, community-based care, PC units, and inpatient consultation teams in integration, respectively. Process indicators of integration include interdisciplinary PC teams (n = 72), simultaneous care approach (n = 71), routine symptom screening (n = 25), PC guidelines (n = 33), care pathways (n = 11), and combined tumor boards (n = 10). A total of 66 articles (65%) mentioned early involvement of PC, 18 (18%) provided a specific timing, and 28 (28%) discussed referral criteria. A total of 45 articles (45%), 20 articles (20%), and 66 articles (65%) discussed 8, 4, and 9 indicators related to the educational, research, and administrative aspects of integration, respectively. CONCLUSION: Integration was a heterogeneously defined concept. Our systematic review highlighted 38 clinical, educational, research, and administrative indicators. With further refinement, these indicators may facilitate assessment of the level of integration of oncology and PC.

How well is palliative care integrated into cancer care? A MASCC, ESMO, and EAPC Project.

INTRODUCTION: The benefits of integration of palliative care into oncology have become evidence-based. How palliative care is perceived and structured in various settings and countries would be of interest. METHOD: We used a previously published questionnaire to survey multiple institutions with members in MASCC and ESMO. The survey was made available on the MASCC website for approximately 6 months and repeated requests were made to complete the survey. Comparisons were made between NCI/ESMO designated cancer centers, nondesignated cancer centers, and urban hospitals. RESULTS: One hundred eighty-three different institutions completed this survey, 28 % of ESMO designated centers. Most institutions had palliative care programs and most programs consisted of an inpatient consult service and outpatient clinics. A minority had inpatient palliative care beds and institution supported hospice services. Barriers to palliative care were largely financial. Integration of palliative care into oncology was highly desirable but only a minority of respondents felt that their institution would financially support expanded services and additional palliative care personnel. Designated centers were more likely to have expanded palliative care services. DISCUSSION: Our findings are very similar to those previously published. Multiple studies have demonstrated that though palliative care integration into oncology is highly beneficial as measured by patient related outcomes, there is a great concern about reimbursement for services and budget constraints which prevent expansion of services. CONCLUSION: Palliative care integration into cancer care is largely through consulting services for inpatients and outpatient clinics. Financial concerns limit integration and expansion of palliative care services. Designated cancer centers have more extensive palliative care services relative to nondesignated cancer centers and urban hospitals.

MASCC/ESMO/EAPC survey of palliative programs.

BACKGROUND: Palliative care program structure is important to integrating palliative services into cancer care. A first step in understanding the structure of palliative care programs is to survey existing programs. METHOD: This data was generated from members of MASCC, the European Society of Medical Oncology (ESMO), and the European Association of Palliative Care (EAPC) who completed the surveys on the website. A survey questionnaire was developed using the survey tool developed by Dr. Hui and colleagues by permission which was modified for the purposes of this study. Findings were described in number and percentages. Inferential statistics involved the Fisher's exact test for factors with two levels, chi-Square test for unordered categorical factors with greater than two levels, Cochran-Armitage trend test for ordered categorical factors, and the Wilcoxon rank sum test for measured factors. RESULTS: Sixty-two program leaders completed the survey. Most programs had been in existence greater than 5 years and were led by oncology trained physicians who had an additional specialty. Most programs had consultative services and outpatient clinics with fewer having inpatient beds and institutionally associated hospices. Most programs provided patient continuity. Patients were generally seen late in the course of illness with the average survival of 23 days when seen as inpatients and 40 days when seen as outpatients. Less than half had palliative care fellowship training programs. Most had research structures in place. DISCUSSION: These findings differ from results reported in a previous survey which may reflect a European palliative care program structure. However, there were similarities which include a high inpatient palliative care unit mortality and short survival of patients seen as outpatients, indicating that referrals to palliative care occur late in the course of cancer. CONCLUSIONS: This study not only differs in some respects to a previous survey of palliative care programs but also confirms the late referral of patients to palliative care.

Use of non-opioid analgesics as adjuvants to opioid analgesia for cancer pain management in an inpatient palliative unit: does this improve pain control and reduce opioid requirements?

BACKGROUND: Cancer pain is complex, and despite the introduction of the WHO cancer pain ladder, few studies have looked at the prevalence of adjuvant medication use in an inpatient palliative medicine unit. In this study, we evaluate the use of adjuvant pain medications in patients admitted to an inpatient palliative care unit and whether their use affects pain scores or opiate dosing. METHODS: In this retrospective observational study, patients admitted to the inpatient palliative care unit over a 3-month period with a diagnosis of cancer on opioid therapy were selected. Data pertaining to demographics, diagnosis, oral morphine dose equivalent of the opioid at the time of discharge, adjuvant analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), and pain scores as reported by nurses and physicians were collected. RESULTS: Seventy-seven patients were eligible over a 3-month period, out of which 65 (84 %) were taking an adjuvant medication. The most commonly prescribed adjuvant was gabapentin (70 %). Fifty-seven percent were taking more than one adjuvant. There were more women in the group receiving adjuvants (57 vs. 17%, p = 0.010). Those without adjuvants compared with those on adjuvants did not have worse pain scores on discharge as reported by physicians (0.8 ± 0.8 vs. 1.0 ± 0.7, p = 0.58) or nurses (2.0 ± 2.7 vs. 2.1 ± 2.6, p = 0.86). There was no difference in morphine equivalent doses of the opioid in both groups (median (min, max); 112 (58, 504) vs. 200 (30, 5,040)) at the time of discharge; 75-80 % of patients had improvement in pain scores as measured by a two-point reduction in numerical rating scale (NRS). DISCUSSION: This study shows that adjuvant medications are commonly used for treating pain in patients with cancer. More than half of study population were on two adjuvants or an adjuvant plus NSAID along with an opioid. We did not demonstrate any benefit in terms of improved pain scores or opioid doses with adjuvants, but this could reflect confounding variables and physician choice. Larger prospective studies are needed to define the opioid-sparing effects of adjuvants. CONCLUSION: Adjuvant agents are used in over 80 % of those treated for cancer pain.

Characterizing fatigue associated with sunitinib and its impact on health-related quality of life in patients with metastatic renal cell carcinoma.

BACKGROUND: Using phase 3 trial data for sunitinib versus interferon (IFN)-α in treatment-naive patients with metastatic renal cell carcinoma, retrospective analyses characterized sunitinib-associated fatigue and its impact on patient-reported health-related quality of life (HRQoL). METHODS: Patients received sunitinib at a dose of 50 mg/day on a schedule of 4 weeks on/2 weeks off (375 patients) or IFN-α at a dose of 9 MU subcutaneously 3 times per week (360 patients). HRQoL was self-assessed using the Functional Assessment of Cancer Therapy-Kidney Symptom Index-15-item (FKSI-15) questionnaire, with fatigue assessed using its Disease-Related Symptoms subscale. Fatigue was also assessed by providers using Common Terminology Criteria for Adverse Events (CTCAE). A repeated-measures model (M1) and random intercept-slope model (M2) characterized sunitinib-associated fatigue over time. Another repeated-measures model examined the relationship between HRQoL scores and CTCAE fatigue grade. RESULTS: M1 demonstrated that the initial increase in patient-reported fatigue with sunitinib was worst during cycle 1, with mean values numerically better at subsequent cycles; most pairwise comparisons of consecutive CTCAE fatigue cycle means were not found to be statistically significant. M2 demonstrated that the overall trend (slope) for patient-reported and CTCAE fatigue with sunitinib was not statistically different from 0. The relationship between most HRQoL scores and CTCAE fatigue was close to linear regardless of treatment, with lower scores (worse HRQoL) corresponding to higher fatigue grade. The majority of HRQoL scores were better with sunitinib versus IFN-α for the same CTCAE fatigue grade. CONCLUSIONS: Patients reported worse fatigue during the first sunitinib cycle. However, in subsequent consecutive cycles, less fatigue was reported with no statistically significant worsening. CTCAE fatigue assessment may not fully capture patient treatment experience.

Fighting insomnia and battling lethargy: the yin and yang of palliative care.

There is an interdependent relationship between insomnia and fatigue in the medical literature, but both remain distinct entities. Insomnia entails problematic sleep initiation, maintenance, or restoration with an accompanying decrease in perceived daytime function. Lethargy is a symptom that has a wide differential diagnosis that heavily overlaps with cancer-related fatigue; however, insomnia may contribute to worsened fatigue and lethargy in cancer patients. Insomnia is a major risk factor for mood disturbances such as depression, which may also contribute to lethargy in this at-risk population. The pathophysiology of fatigue and insomnia is discussed in this review, including their differential diagnoses as well as the emerging understanding of the roles of neurotransmitters, branched-chain amino acids, and inflammatory cytokines. Treatment approaches for insomnia and fatigue are also discussed and reviewed, including the role of hypnotics, psychotropics, hormonal agents, and alternative therapies.

Novel drug treatments for pain in advanced cancer and serious illness: a focus on neuropathic pain and chemotherapy-induced peripheral neuropathy.

Drugs that are commercially available but have novel mechanisms of action should be explored as analgesics. This review will discuss haloperidol, miragabalin, palmitoylethanolamide (PEA), and clonidine as adjuvant analgesics or analgesics. Haloperidol is a sigma-1 receptor antagonist. Under stress and neuropathic injury, sigma-1 receptors act as a chaperone protein, which downmodulates opioid receptor activities and opens several ion channels. Clinically, there is only low-grade evidence that haloperidol improves pain when combined with morphine, methadone, or tramadol in patients who have cancer, pain from fibrosis, radiation necrosis, or neuropathic pain. Miragabalin is a gabapentinoid approved for the treatment of neuropathic pain in Japan since 2019. In randomized trials, patients with diabetic neuropathy have responded to miragabalin. Its long binding half-life on the calcium channel subunit may provide an advantage over other gabapentinoids. PEA belongs to a group of endogenous bioactive lipids called ALIAmides (autocoid local injury antagonist amides), which have a sense role in modulating numerous biological processes in particular non-neuronal neuroinflammatory responses to neuropathic injury and systemic inflammation. Multiple randomized trials and meta-analyses have demonstrated PEA's effectiveness in reducing pain severity arising from diverse pain phenotypes. Clonidine is an alpha2 adrenoceptor agonist and an imidazoline2 receptor agonist, which is U.S. Federal Drug Administration approved for attention deficit hyperactivity disorder in children, Tourette's syndrome, adjunctive therapy for cancer-related pain, and hypertension. Clonidine activation at alpha2 adrenoceptors causes downstream activation of inhibitory G-proteins (Gi/Go), which inhibits cyclic Adenosine monophosphate (AMP) production and hyperpolarizes neuron membranes, thus reducing allodynia. Intravenous clonidine has been used in terminally ill patients with poorly controlled symptoms, in particular pain and agitation.