TY - JOUR
AU - Inoue,, Akira
AB - Abstract 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. adjuvant analgesics, analgesics, cancer pain, palliative care, refractory pain Introduction Pain is a common symptom in cancer patients, with a prevalence of 66.4% in advanced, metastatic or terminal-stage patients (1). Among them, moderate-to-severe pain was reported by 55.1% of patients; ~20–40% of patients experiencing pain are inadequately relieved by standard analgesic treatments including opioids, acetaminophen and non-steroidal anti-inflammatory drugs (1–5). When patients with cancer pain respond poorly to the abovementioned analgesics, they are often prescribed adjuvant analgesics including corticosteroids, antidepressants, anticonvulsants and topical agents in combination (4,5). The World Health Organization and the National Comprehensive Cancer Network guidelines also indicated that adjuvant analgesics have been beneficial in the management of cancer pain syndromes in conjunction with opioids (4,5). Caraceni et al. (6) reported in 1999 that adjuvant analgesics were administered to 36.2% of patients with cancer pain, and its usage rate and standard use may be changing since new adjuvant analgesics have been developed. However, only a few studies have reported the standard use of adjuvant analgesics for cancer pain in recent clinical practices. Adjuvant analgesics are often used with opioids for cancer pain that is resistant to standard analgesic treatments and cancer-related neuropathic pain (4,5,7–9); however, strong evidence for such a practice is limited. One possible reason is that previous clinical trials, including some randomized controlled trials, have evaluated their effectiveness only for a non-specific pathophysiology of cancer pain, although World Health Organization (WHO) guidelines for the management of cancer pain suggested that adjuvant analgesics should be selected according to the specific pathophysiology of cancer pain (4). In addition, cancer pain has been treated with adjuvant analgesics according to the evidence of chronic pain or non-cancer neuropathic pain; however, the differences in the use of adjuvant analgesics between cancer pain and chronic pain can vary widely (5,7). Hence, a survey on the current use of adjuvant analgesics for cancer pain in real practice is imperative should further research on their effectiveness against cancer pain be conducted. The primary aim of this survey was to investigate the preliminary data on the current use of adjuvant analgesics for cancer pain that responds poorly to opioids by certified palliative care specialists (PCSs). In particular, we tried to clarify the choice of adjuvant analgesics depending on each pathophysiological mechanism of cancer pain in the palliative care specialty. Patients and methods Subjects This nationwide cross-sectional and questionnaire-based survey was conducted online and aimed at all national PCS registries of the Japanese Society of Palliative Medicine (JSPM) between April and May 2018. The office of JSPM sent an invitation to 208 PCS via email, with two subsequent reminders. The electronic data, including respondent backgrounds (age, sex, work environment and palliative care experience) and responses to the self-reported questionnaire regarding the use of adjuvant analgesics for cancer pain that responds poorly to opioids, were collected through an online website using KINTONE (Cybozu, Japan) (7). The researchers could not access the list of participants. The PCS who could not receive the JSPM invitation, declined to participate or did not reply were excluded from further analyses. This study was part of a series of ‘Attitude of Japanese PCSs towards adjuvant analgesics in cancer patients with pain’ (7) and was approved by the independent ethics committee of Tohoku University School of Medicine (Approval No. 2017-1-998). Questionnaire Because of the lack of an existing specific questionnaire, we developed an ad hoc questionnaire on the basis of literature reviews, discussion among our group and pilot testing. In this survey, we defined refractory cancer pain as the pain that is poorly responsive to opioids, even after titrating up the opioid doses adequately until the level of intolerance that can cause opioid-induced side effects is reached (4,5,8,9). PCS were supposed to exclude methadone from those opioids because of its N-methyl-d-aspartate receptor antagonist mechanism, which inhibits neural excitation similar to that observed with ketamine (10). In the questionnaire, PCSs were questioned on the use of adjuvant analgesics for refractory cancer pain in current clinical practices. They were supposed to use adjuvant analgesics for patients with refractory cancer pain whose Karnofsky Performance Status was ≥50 with an expected prognosis of ≥1-month survival (7,11). In addition, they were supposed to select the dose of each adjuvant analgesics for patients with refractory cancer pain who did not have any organ dysfunction. There were three questions on the rate of prescribing adjuvant analgesics in refractory cancer pain and on the start of the timing of adjuvant analgesics after the opioid doses were uptitrated—(i) How often do you use adjuvant analgesics for refractory cancer pain in patients with cancer pain in a year? (ii) How often do you use each of these adjuvant analgesics (amitriptyline, amoxapine, duloxetine, other selective serotonin reuptake inhibitors, pregabalin, gabapentin, ketamine, dexamethasone/betamethasone, prednisolone, lidocaine/mexiletine (sodium channel blockers), butyl bromide, clonazepam and others (12) (zoledronic acid and denosumab for cancer-induced bone pain were excluded because their current use guidelines for cancer pain have already been set) in a year for patients with refractory cancer pain? and (iii) To what strength of opioids do you titer up before it is found ineffective for refractory cancer pain and start adjuvant analgesics [we calculated the dose of opioids as the oral morphine equivalent daily dose (MEDD) in milligrams per day]? The survey also included the following three questions on how to use pregabalin, dexamethasone/betamethasone, lidocaine and ketamine for refractory cancer pain—(i) How effective do you think each adjuvant analgesic is for each pathophysiological mechanism of cancer pain? (ii) What is the initiating dose (enable to be effective in a few days) of each adjuvant analgesics per day? and (iii) How long is the time to the first response in each adjuvant analgesics therapy? In question (i), the pathophysiological mechanism of cancer pain was generated based on ‘cancer pain syndrome’ (8), and its validity on the use and effectiveness of each analgesic therapy in real practice was predefined in our groups (Table 1). The PCS evaluated the effectiveness of each analgesic therapy (pregabalin, dexamethasone/betamethasone, lidocaine and ketamine, respectively) for each pathophysiological mechanism of cancer pain using a 6-point Likert scale (strongly agree, agree, agree a little, disagree a little, disagree and strongly disagree). In addition, we asked PCS about other pathophysiological mechanisms of cancer pain for which any of these analgesic therapies were effective. Table 1 The questions about effective pathophysiology of cancer pain in each adjuvant analgesic therapy (pregabalin, dexamethasone/betamethasone, lidocaine and ketamine, respectively) Variables . Pregabalin . Dexamethasone/betamethasone . Lidocaine . Ketamine . Head and neck neoplasm-related paina ○b ○ ○ ○ Malignant painful radiculopathy ○ ○ ○ ○ Malignant perineal pain or tenesmus ○ ○ ○ ○ Neuropathic pain caused by tumor-related spinal cord compression ○ ○ ○ ○ Peripheral neuropathic pain with hypersensitivity, hyperalgesia or allodynia ○ ○ ○ ○ Tumor invasion of abdominal organs-related paina ○ ○ ○ ○ Tumor-related bone pain ○ ○ ○ Peritoneal carcinomatosis-related abdominal paina ○ ○ ○ Brain tumor or leptomeningeal metastases related headache ○ Hepatic distention syndrome-related visceral pain ○ Malignant intestinal obstruction related visceral pain ○ Tumor-related soft tissue pain (ex. skin or mucosa) ○ Variables . Pregabalin . Dexamethasone/betamethasone . Lidocaine . Ketamine . Head and neck neoplasm-related paina ○b ○ ○ ○ Malignant painful radiculopathy ○ ○ ○ ○ Malignant perineal pain or tenesmus ○ ○ ○ ○ Neuropathic pain caused by tumor-related spinal cord compression ○ ○ ○ ○ Peripheral neuropathic pain with hypersensitivity, hyperalgesia or allodynia ○ ○ ○ ○ Tumor invasion of abdominal organs-related paina ○ ○ ○ ○ Tumor-related bone pain ○ ○ ○ Peritoneal carcinomatosis-related abdominal paina ○ ○ ○ Brain tumor or leptomeningeal metastases related headache ○ Hepatic distention syndrome-related visceral pain ○ Malignant intestinal obstruction related visceral pain ○ Tumor-related soft tissue pain (ex. skin or mucosa) ○ aNociceptive pain, neuropathic pain or mixed pain of them. bQuestioned at questionnaire. Open in new tab Table 1 The questions about effective pathophysiology of cancer pain in each adjuvant analgesic therapy (pregabalin, dexamethasone/betamethasone, lidocaine and ketamine, respectively) Variables . Pregabalin . Dexamethasone/betamethasone . Lidocaine . Ketamine . Head and neck neoplasm-related paina ○b ○ ○ ○ Malignant painful radiculopathy ○ ○ ○ ○ Malignant perineal pain or tenesmus ○ ○ ○ ○ Neuropathic pain caused by tumor-related spinal cord compression ○ ○ ○ ○ Peripheral neuropathic pain with hypersensitivity, hyperalgesia or allodynia ○ ○ ○ ○ Tumor invasion of abdominal organs-related paina ○ ○ ○ ○ Tumor-related bone pain ○ ○ ○ Peritoneal carcinomatosis-related abdominal paina ○ ○ ○ Brain tumor or leptomeningeal metastases related headache ○ Hepatic distention syndrome-related visceral pain ○ Malignant intestinal obstruction related visceral pain ○ Tumor-related soft tissue pain (ex. skin or mucosa) ○ Variables . Pregabalin . Dexamethasone/betamethasone . Lidocaine . Ketamine . Head and neck neoplasm-related paina ○b ○ ○ ○ Malignant painful radiculopathy ○ ○ ○ ○ Malignant perineal pain or tenesmus ○ ○ ○ ○ Neuropathic pain caused by tumor-related spinal cord compression ○ ○ ○ ○ Peripheral neuropathic pain with hypersensitivity, hyperalgesia or allodynia ○ ○ ○ ○ Tumor invasion of abdominal organs-related paina ○ ○ ○ ○ Tumor-related bone pain ○ ○ ○ Peritoneal carcinomatosis-related abdominal paina ○ ○ ○ Brain tumor or leptomeningeal metastases related headache ○ Hepatic distention syndrome-related visceral pain ○ Malignant intestinal obstruction related visceral pain ○ Tumor-related soft tissue pain (ex. skin or mucosa) ○ aNociceptive pain, neuropathic pain or mixed pain of them. bQuestioned at questionnaire. Open in new tab Data analysis We used descriptive statistics including percentages, frequencies and quartiles to describe participants’ characteristics and their responses to the questionnaire. For the question on the effective pathophysiological mechanism of cancer pain in each adjuvant analgesic therapy, ‘Strongly agree’, ‘Agree’ and ‘Agree a little’ were combined and coded as ‘effectiveness’ in our analysis. All analyses were performed using IBM SPSS Statistics, version 22 (IBM, Armonk, NY, USA). Results Characteristics of palliative care physicians Of the 208 PCS sampled, 87 completed the questionnaire (response rate of 41.8%) (Table 2). Of these, 29 responses to the question regarding the frequency of using clonazepam for refractory cancer pain were not available due to web system errors. Other questions were answered in full by the 87 responders. Among the respondents, 77% were male and their work environments included: palliative care units or inpatient hospices (39 specialists; 44.8%), palliative care teams at general hospital (35; 40.2%), home care services (7; 8%) and others (6; 6.9%). Their median number of years of palliative care experience was 11 [interquartile range (IQR) 9–15]. Table 2 Demographics and characteristics of certified palliative care specialists, and their opinion of use adjuvant analgesics for refractory cancer pain Variables (n = 87) . n (%) . Age (years) Mean (SDa) 45 (11.7) Gender Male 67 (77.0) Female 20 (23.0) Work environments Palliative care units or inpatient hospices 39 (44.8) Palliative care teams at general hospital 35 (40.2) Home care services 7 (8.0) Others 6 (6.9) Palliative care experience (number of years, median; IQRa) 11 (9–15) Patients (per year, median; IQR) Number of cancer patients 120 (85–250) Number of cancer patients with pain 90 (50–155) Proportion of cancer patients with pain (%)b 70 (60–80) Number of patients with cancer pain who use adjuvant analgesics for refractory cancer painc 36 (15–60) Proportion of patients with cancer pain who use adjuvant analgesics for refractory cancer pain (%)d 40 (20–73) Proportion of adjuvant analgesics used for refractory cancer paine (per year, %, median; IQR) Pregabalin 60 (40.0–80.0) Dexamethasone/betamethasone 20 (10.0–50.0) Duloxetine 20 (10.0–30.0) Ketamine 5 (0–12.5) ClassIb antiarrhythmicsf 5 (0–10.0) Clonazepamg 0 (0–7.3) Butyl scopolamine 0 (0–3.0) Dose of opioids after dose titration when adjuvant analgesics were administered to patients with refractory cancer pain MEDD (mg, median; IQR) 60 (30–80) Variables (n = 87) . n (%) . Age (years) Mean (SDa) 45 (11.7) Gender Male 67 (77.0) Female 20 (23.0) Work environments Palliative care units or inpatient hospices 39 (44.8) Palliative care teams at general hospital 35 (40.2) Home care services 7 (8.0) Others 6 (6.9) Palliative care experience (number of years, median; IQRa) 11 (9–15) Patients (per year, median; IQR) Number of cancer patients 120 (85–250) Number of cancer patients with pain 90 (50–155) Proportion of cancer patients with pain (%)b 70 (60–80) Number of patients with cancer pain who use adjuvant analgesics for refractory cancer painc 36 (15–60) Proportion of patients with cancer pain who use adjuvant analgesics for refractory cancer pain (%)d 40 (20–73) Proportion of adjuvant analgesics used for refractory cancer paine (per year, %, median; IQR) Pregabalin 60 (40.0–80.0) Dexamethasone/betamethasone 20 (10.0–50.0) Duloxetine 20 (10.0–30.0) Ketamine 5 (0–12.5) ClassIb antiarrhythmicsf 5 (0–10.0) Clonazepamg 0 (0–7.3) Butyl scopolamine 0 (0–3.0) Dose of opioids after dose titration when adjuvant analgesics were administered to patients with refractory cancer pain MEDD (mg, median; IQR) 60 (30–80) SD, standard deviation; IQR, interquartile range; MEDD, morphine equivalent daily dose. aInterquartile range. bOf cancer patients in a year. cDefined as a pain being poorly responsive to opioids even though dose of it is up adequately titrated until intolerance to opioid-induced side effects. dOf patients with cancer pain in a year. eOf patients with refractory cancer pain in a year. fLidocaine and mexitylene (sodium channel blocker). gTwenty-nine responses were unknown due to web system errors. Open in new tab Table 2 Demographics and characteristics of certified palliative care specialists, and their opinion of use adjuvant analgesics for refractory cancer pain Variables (n = 87) . n (%) . Age (years) Mean (SDa) 45 (11.7) Gender Male 67 (77.0) Female 20 (23.0) Work environments Palliative care units or inpatient hospices 39 (44.8) Palliative care teams at general hospital 35 (40.2) Home care services 7 (8.0) Others 6 (6.9) Palliative care experience (number of years, median; IQRa) 11 (9–15) Patients (per year, median; IQR) Number of cancer patients 120 (85–250) Number of cancer patients with pain 90 (50–155) Proportion of cancer patients with pain (%)b 70 (60–80) Number of patients with cancer pain who use adjuvant analgesics for refractory cancer painc 36 (15–60) Proportion of patients with cancer pain who use adjuvant analgesics for refractory cancer pain (%)d 40 (20–73) Proportion of adjuvant analgesics used for refractory cancer paine (per year, %, median; IQR) Pregabalin 60 (40.0–80.0) Dexamethasone/betamethasone 20 (10.0–50.0) Duloxetine 20 (10.0–30.0) Ketamine 5 (0–12.5) ClassIb antiarrhythmicsf 5 (0–10.0) Clonazepamg 0 (0–7.3) Butyl scopolamine 0 (0–3.0) Dose of opioids after dose titration when adjuvant analgesics were administered to patients with refractory cancer pain MEDD (mg, median; IQR) 60 (30–80) Variables (n = 87) . n (%) . Age (years) Mean (SDa) 45 (11.7) Gender Male 67 (77.0) Female 20 (23.0) Work environments Palliative care units or inpatient hospices 39 (44.8) Palliative care teams at general hospital 35 (40.2) Home care services 7 (8.0) Others 6 (6.9) Palliative care experience (number of years, median; IQRa) 11 (9–15) Patients (per year, median; IQR) Number of cancer patients 120 (85–250) Number of cancer patients with pain 90 (50–155) Proportion of cancer patients with pain (%)b 70 (60–80) Number of patients with cancer pain who use adjuvant analgesics for refractory cancer painc 36 (15–60) Proportion of patients with cancer pain who use adjuvant analgesics for refractory cancer pain (%)d 40 (20–73) Proportion of adjuvant analgesics used for refractory cancer paine (per year, %, median; IQR) Pregabalin 60 (40.0–80.0) Dexamethasone/betamethasone 20 (10.0–50.0) Duloxetine 20 (10.0–30.0) Ketamine 5 (0–12.5) ClassIb antiarrhythmicsf 5 (0–10.0) Clonazepamg 0 (0–7.3) Butyl scopolamine 0 (0–3.0) Dose of opioids after dose titration when adjuvant analgesics were administered to patients with refractory cancer pain MEDD (mg, median; IQR) 60 (30–80) SD, standard deviation; IQR, interquartile range; MEDD, morphine equivalent daily dose. aInterquartile range. bOf cancer patients in a year. cDefined as a pain being poorly responsive to opioids even though dose of it is up adequately titrated until intolerance to opioid-induced side effects. dOf patients with cancer pain in a year. eOf patients with refractory cancer pain in a year. fLidocaine and mexitylene (sodium channel blocker). gTwenty-nine responses were unknown due to web system errors. Open in new tab Of cancer patients receiving medical treatment by PCS, the median prevalence of cancer pain was 70% (IQR; 60–80) and the median number of patients was 90 (50–155) per year. Of those patients with cancer pain, the median prevalence of those who prescribed adjuvant analgesics for refractory cancer pain was 40% (20–73) and the median number of patients was 36 (15–60) per year (Table 2). When PCS started to use adjuvant analgesics for patients with refractory cancer pain, the median dose of opioids was 60 (IQR, 30–80) mg on MEDD after its dose was uptitrated. The most frequently used adjuvant analgesic for refractory cancer pain was pregabalin [median; 60% IQR (40–80)] (Table 2). Among PCS using gabapentinoids, all prescribed pregabalin more often than gabapentin [0% (0–0)]. Adjuvant analgesics for refractory cancer pain not only included pregabalin but also dexamethasone/betamethasone [20% (10–50)] and duloxetine [20% (10–30)] (Table 2). The effective pathophysiological mechanism of cancer pain in each adjuvant analgesics therapy Figure 1 presents the responses on effective pathophysiological mechanisms of cancer pain for prescribing pregabalin, dexamethasone/betamethasone, lidocaine and ketamine answered by PCS, respectively. Most PCS considered pregabalin as effective for malignant painful radiculopathy (n = 81, 93.1%), dexamethasone/betamethasone for neuropathic pain caused by tumor-related spinal cord compression (n = 82, 94.3%), lidocaine for pain related to metastasis in abdominal organs (n = 59, 67.8%) and ketamine for tumor-related bone pain (n = 63, 72.4%). Although we asked PCS about other pathophysiological mechanisms of cancer pain whose effectiveness can correspond to each analgesic therapy, we received only a few responses: pregabalin for referred pain (n = 1), thalamic pain (n = 1) and neuropathic pain caused by central sensitization with shooting pain (n = 1); dexamethasone/betamethasone for neuropathic pain caused by Pancoast–Tobias syndrome (n = 1) and nociceptive pain caused by mediastinal lymph node hyperplasia (n = 1); and lidocaine for skin-burning pain (n = 1), hepatic distention syndrome-related nociceptive pain (n = 1), tumor-related soft tissue pain (n = 1) and tumor-related bone pain (n = 1). Figure 1 Open in new tabDownload slide Open in new tabDownload slide The effective pathophysiological mechanism of cancer pain of (a) pregabalin, (b) dexamethasone/betamethasone, (c) lidocaine and (d) ketamine in the treatment of cancer pain based on the evaluation of responses by certified palliative care specialists with a 6-point Likert scale (strongly agree, agree, agree a little, disagree a little, disagree and strongly disagree). ‘Strongly agree’, ‘Agree’ and ‘Agree a little’ were combined and coded as ‘Effectiveness’. *Pain; nociceptive pain, neuropathic pain or mixed pain with nonspecific etiology. Figure 1 Open in new tabDownload slide Open in new tabDownload slide The effective pathophysiological mechanism of cancer pain of (a) pregabalin, (b) dexamethasone/betamethasone, (c) lidocaine and (d) ketamine in the treatment of cancer pain based on the evaluation of responses by certified palliative care specialists with a 6-point Likert scale (strongly agree, agree, agree a little, disagree a little, disagree and strongly disagree). ‘Strongly agree’, ‘Agree’ and ‘Agree a little’ were combined and coded as ‘Effectiveness’. *Pain; nociceptive pain, neuropathic pain or mixed pain with nonspecific etiology. The initiating dose and time period to the first response in each adjuvant analgesics therapy The median dose of initiating amount of pregabalin, dexamethasone/betamethasone, lidocaine and ketamine was 75 (IQR, 50–150) mg/day, 4 (IQR, 4–4) mg/day, 200 (IQR, 100–400) mg/day and 50 (IQR, 20–100) mg/day, respectively. The median period of time to the first response in pregabalin, dexamethasone/betamethasone, lidocaine and ketamine was 5 (IQR, 3–7) days, 3 (IQR, 3–5) days, 2 (IQR, 1–3) days and 3 (IQR, 1–3) days, respectively. Discussion To the best of our knowledge, this is the first nation-wide investigation on practices among PCS regarding the routine clinical use of adjuvant analgesics for cancer pain with poor response to opioids. The strength of this study is that we could present not only the usage frequency of adjuvant analgesics for cancer pain but also detail their recent use in clinical practices, especially regarding their selection basis, dose titration and starting doses. This study showed that many PCSs routinely select adjuvant analgesics depending on the specific pathophysiological mechanisms of cancer pain and the cancer pain syndrome in each case. In particular, more than 80% of PCS answered that pregabalin might be effective for malignant painful radiculopathy, tumor-related spinal cord compression and head and neck neoplasm-related pain (93.1, 85.1 and 82.8%, respectively) and that dexamethasone/betamethasone might be effective for neuropathic pain caused by tumor-related spinal cord compression, brain tumor or leptomeningeal metastases-related headache and malignant intestinal obstruction-related visceral pain (94.3, 86.2 and 85.1, respectively) (Fig. 1). Some previous studies suggested that pregabalin might be effective in the treatment of cancer pain and cancer-related neuropathic pain that are poorly responsive to opioids therapy (5,13–16); however, a few systematic reviews did not recommend the use of pregabalin in such cases due to insufficient evidence despite its wide prescription-based use (4, 17). Regarding corticosteroids for cancer pain, our findings are similar to those of studies detaining the guidelines, which supported its effectiveness, especially for cancer-related neuropathic pain and visceral pain (4,5,18–20). Meanwhile, few previous studies compared corticosteroids to placebo and could not provide any evidence of analgesia for cancer pain with corticosteroids (21,22). Paulsen et al. (21) compared the effectiveness of methylprednisolone to that of placebo and could not demonstrate any effectiveness; however, the authors evaluated patients with non-specific pathophysiological mechanisms of cancer pain and excluded those with severe cancer pain due to spinal cord compression for which corticosteroids might be useful according to our results. Our findings indicate that clinicians recommend pregabalin and corticosteroids depending on specific pathophysiological mechanisms of cancer pain; however, there have been few studies to investigate whether the pathophysiology-based or empiric approach of adjuvant analgesics is superior in patients with cancer pain. Thus, future clinical trials of adjuvant analgesics should emphasize on the specific pathophysiological mechanisms of cancer pain for which they may be effective and compare the effectiveness of this approach to that of the non-specific empirical approach. Our study indicated that the starting dose of adjuvant analgesics for cancer pain might be lower and the time period to the first response might be shorter than that for non-cancer chronic pain. In regard to pregabalin, PCS reported that the median starting dosage for cancer pain was 75 mg/day and the median time to receive the first response was 5 days, although previous studies recommended that the starting dose of pregabalin to be 150–300 mg/day and the waiting period to be more than a week for judging its efficacy in non-cancer chronic pain (23,24). However, some clinical trials investigated the efficacy of pregabalin for non-cancer chronic pain daily, every few days and weekly (24–26); Stacey et al. (25) showed that the time to the onset of pain relief in pregabalin was 1.5–3.5 days. Garassino et al. designed their clinical trial with a starting dose of 50 mg/day pregabalin and increased the dose daily (if the subjects had ≥4/10 on prior 24-hour average pain scores and no side effects) and reported achieving analgesia with a mean dose of 100 mg/day. Raptis et al. designed their clinical trial with a starting dose of 75 mg/day and increased the dose every 3 days (or later, based on tolerability) (13,15). WHO guidelines have recommended appropriate doses of corticosteroids including an initiation dose and optimal maintenance periods including the time period to the first response for their use as adjuvant analgesics (4). In our study, PCS reported that the median starting dose of dexamethasone/betamethasone for cancer pain was 4 mg/day and the median period of time to the first response was 3 days. These findings suggest that adjuvant analgesics for cancer pain can be started at a lower dose than that for non-cancer chronic pain and can be uptitrated rapidly; however, further studies are required to understand how to use such analgesics. In our study, the median dose of opioids after dose uptitration was 60 mg of MEDD when adjuvant analgesics were administered to patients with refractory cancer pain, which was poorly responsive to opioids therapy. Some guidelines have identified that refractory cancer pain is not relieved by the use of analgesics including opioids and recommended that adjuvant analgesics should be used for such opioid-refractory cancer pain (4,5,8,9). The 60 mg of MEDD in this study may be relatively lower than that used in other countries because the consumption of opioids in Japanese cancer patients (per capita) has been lower than that in other countries, especially European countries and the United States. Furthermore, the authors of this study had not heard of the type of opioids that may have an impact on the quality of pain management. However, there has been no consensus on the sufficient dose of opioid when adjuvant analgesics should be used for opioid-refractory cancer pain. Thus, our study suggests that 60 mg of MEDD may be one of the community standards at which PCS consider the use of analgesic adjutants for refractory cancer pain. This study has a few limitations. First, the questionnaires were not validated, and Japanese PCS-reported practice might not be representative of practices worldwide. Second, this study has a low response rate and small sample size. There is a shortage of PCS in Japan and the email invitation could have been overlooked or forgotten. Third, as with all survey-based studies, there is vulnerability to a non-response bias if non-respondents differed systematically from respondents. However, we could not get information on non-responders since they did not provide consent to the survey by responding to the questionnaire. There is a possibility that the way adjuvant analgesics are used in the real world is different than that reported in this study since our results are based on expert opinions and not from a clinical study with targeted patients. Finally, responses from PCS could be influenced by recall bias and social desirability bias. We only selected those PCS as respondents who possess a certain degree of knowledge of palliative care. On the other hand, the respondents in the present survey were relatively young (median age, 45 years) and did not have many years of palliative care experience (11 years). We did not investigate the true number of patients treated with adjuvant analgesics. Collectively, the findings of the present study cannot be generalized. In summary, we might indicate the current use of adjuvant analgesics for cancer pain, especially since many PCSs are selecting adjuvant analgesics depending on the specific pathophysiological mechanism of cancer pain. 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TI - The current clinical use of adjuvant analgesics for refractory cancer pain in Japan: a nationwide cross-sectional survey
JF - Japanese Journal of Clinical Oncology
DO - 10.1093/jjco/hyaa147
DA - 2020-12-16
UR - https://www.deepdyve.com/lp/oxford-university-press/the-current-clinical-use-of-adjuvant-analgesics-for-refractory-cancer-tffk40wK2K
SP - 1434
EP - 1441
VL - 50
IS - 12
DP - DeepDyve
ER -