We previously demonstrated that select cytokine gene polymorphisms in interleukin (IL)-8 are a significant predictor for pain and analgesia in patients with lung cancer. This study explores the role of thirteen potentially functional polymorphisms in cytokine genes including IL-1β, IL-6, IL-8, IL-10, IL-18, tumor necrosis factor (TNF-α), and nuclear factor kappa-B subunit 1 (NFkappaB1) in pain severity in patients with pancreatic cancer. We evaluated a series opatients with histologically-confirmed adenocarcinoma of the pancreas (n=484) who had completed a self-administered survey of pain prior to initiating any cancer treatment. DNA (n=156) available for a subset of white patients was assayed and assessed for association with pain severity. Results showed that 26% (128/484) reported experiencing severe pain (score of > 7 on a 0–10 scale). Severe pain varied by stage of disease (odds ratio [OR] Stage II=4.02, 95% confidence interval (CI)=1.07, 15.07; Stage III=5.02, 95% CI=1.28, 19.61; Stage IV=6.90, 95% CI=1.96, 24.29), ethnicity (OR non-Hispanic blacks=3.67; 95% CI=1.44, 9.38), reports of depressed mood (OR=1.94; 95% CI=1.09, 3.43), and female sex (OR=1.78; 95% CI=1.04, 3.05). Controlling for these covariates, IL8-251T/A (OR=2.43, 95% CI=1.3, 4.7, P<0.009) significantly predicted severe pain in a subset of white patients. When we adjusted for reported analgesic use, we found that IL8-251T/A persisted as a predictor for severe pain, with carriers of TT and AT genotypes having more than a threefold risk (OR=3.23, 95% CI=1.4, 4.7) for severe pain relative to the AA genotypes. We provide preliminary evidence of the role of IL-8 in the severity of pain in pancreatic cancer patients. Additional studies are needed in larger cohorts of patients.
Pain; genes; cytokines; epidemiology; cancer; analgesia; molecular epidemiology
Many of the same inflammatory factors that promote tumor growth are also hypothesized to function as pain modulators. There is substantial interindividual variation in pain severity in cancer patients. Therefore, we evaluated 59 SNPs in 37 inflammation genes in newly diagnosed non-Hispanic Caucasian lung cancer patients (n=667) and assessed their association with pain severity. Patients rated their pain “during the past week” on an 11-point numeric scale, (0= ‘no pain’ and 10= ‘pain as bad as you can imagine’) at presentation, prior to initiating cancer therapy. Reported analgesic use was abstracted from charts and converted to an equivalent dose of morphine (MEDD). Results showed that 16% of the patients reported severe pain (score ≥ 7). Advanced stage of disease (OR=2.34; 95% CI=1.50-3.65, p-value=0.001), age≤ 50 (OR=2.10; 95%CI=1.32-3.30, p-value=0.002), reports of depressed mood (OR=3.68; 95%CI=1.96-6.93, p-value=0.001); fatigue (OR=3.72; 95% CI=2.36-5.87, p-value=0.001) and MEDD (OR=1.02; 95% C.I=1.01, 1.03) were significantly correlated with severe pain. Controlling for these non-genetic covariates, we found that patients with CC genotypes for PTGS2 exon10+837T>C (rs5275) were at lower risk for severe pain (OR=0.33; 95% Confidence Interval=0.11-0.97) and an additive model for TNF α -308GA (rs1800629) (OR=1.67, 95% CI=1.08,2.58) and NFKBIA Ex6+50C>T (rs8904) was predictive of severe pain (OR=0.64, 95% CI=0.43,0.93). In a multi-gene analysis, we found a gene-dose effect, with each protective genotype reducing the risk for severe pain by as much as 38%. This study suggests the importance of inflammation gene polymorphisms in modulating pain severity. Additional studies are needed to validate our findings.
Pain; Genes; Inflammation; Epidemiology; Cancer
Pain in terminal cancer patients may be refractory to systemic analgesics or associated with adverse drug reactions to analgesics. Epidural analgesia has been effectively used in such patients for pain control. However, this method does not provide pain relief to all patients. The efficacy and complications of continuous epidural analgesia were evaluated for expanding efficacy in terminal cancer patients.
Materials and Methods
The charts of patients who received epidural analgesia for over 5 years for the control of terminal cancer pain were reviewed retrospectively.
Ninety-six patients received 127 epidural catheters. The mean duration for epidural catheterization was 31.5±55.6 (5-509) days. The dose of epidural morphine increased by 3.5% per day. The efficacy of epidural analgesia at 2 weeks follow up revealed improved pain control (n=56), as the morphine equivalent drug dose dropped from 213.4 mg/day to 94.1 mg/day (p<0.05) at 2 weeks follow up. Accordingly, after 2 weeks institution of epidural analgesia, there was a significant reduction in the proportion of patients with severe pain, from 78.1% to 19.6% (p<0.05).
Epidural analgesia was an effective pain control method in patients with terminal cancer pain, however, a systematized algorithm
for the control of cancer-related pain in needed.
Bupivacaine; cancer pain; epidural analgesia; morphine
The agonist-antagonist kappa-opioid nalbuphine administered for postoperative pain produces greater analgesia in females than in males. In fact, males administered nalbuphine (5 mg) experience pain greater than those receiving placebo, suggesting the existence of an anti-analgesic effect. These sexually dimorphic effects on postoperative pain can be eliminated by co-administration of a fixed ratio of the prototypical opioid receptor antagonist naloxone with nalbuphine, implying a role for opioid receptors in the anti-analgesic as well as analgesic effects of nalbuphine. In the present study, we further evaluated the role of opioid receptors in the sex-specific effects on pain produced by nalbuphine by co-administering a dose of morphine low enough that it does not produce analgesia. Following extraction of bony impacted third molar teeth, nalbuphine (5 mg) was administered alone or in combination with either of two low doses of morphine (2 mg or 4 mg). Both doses of morphine reversed nalbuphine-induced anti-analgesia in males, but only the lower dose (2 mg) reached statistical significance. Neither dose affected nalbuphine-induced analgesia in females, and when administered alone in either males or females, morphine (2 mg) had no analgesic effect. Though not observed in females, the effect of morphine in males argues that, like naloxone, low dose morphine may act as an anti-analgesia opioid receptor antagonist.
Previously we reported that the nalbuphine produces both analgesic and anti-analgesic effects, and that the opioid antagonist naloxone can enhance nalbuphine analgesia by selectively antagonizing the anti-analgesic effect. Here we show that morphine, given in a subanalgesic dose, reverses nalbuphine-induced anti-analgesia in males, perhaps by a similar mechanism.
kappa opioid; sexual dimorphism; analgesia; gender
Chronic cancer and nonmalignant pain (CNMP) is a common and major health problem afflicting approximately 40 million persons in the US. Most cancer patients, and many patients with CNMP, require opioid analgesics to obtain adequate pain relief. Oral oxymorphone is a new formulation of an existing parenteral opioid that has become available for the treatment of significant pain: acute postoperative, chronic arthritis, chronic low back, and chronic cancer pain. Oxymorphone is a typical mu-opioid agonist that is effective in both immediate- and extended-release (IR and ER) formulations. Oxymorphone is more lipid soluble than morphine, resulting in a rapid onset of action when given in tablet formulation, with a duration of action of approximately 4–6 hours in IR and 12 hours in ER preparations. Oxymorphone provides excellent pain relief for significant pain, with typical opioid side effects that are usually mild or moderate in intensity. Multiple double-blind, prospective, placebo-controlled clinical trials have demonstrated the clinical efficacy and safety of this new oral opioid preparation. Oral oxymorphone is an effective opioid that provides a new therapeutic option for the physician.
chronic pain; oxymorphone; opioids; extended-release; sustained-release; cancer pain
Morphine is the core of perioperative pain management. However, when it comes to cancer surgery the possibility that this drug might affect tumor recurrence and metastasis has raised concerns. The results of two recent retrospective clinical trials indicated that regional anesthesia/analgesia might be beneficial in prostate and breast cancer surgery. It was proposed that morphine could be responsible for the higher recurrence and mortality rate observed in the general anesthesia/opioid analgesia groups. Nevertheless, the results of several other retrospective studies and one randomized prospective trial failed to confirm any advantage for regional anesthesia/analgesia over general anesthesia and opioid analgesia. Moreover laboratory data on the effect of morphine on cancer are contradictory, ranging from tumor-promoting to anti-tumor effects. Considering that surgical stress and pain promote the recurrence and spread of cancer, choosing a proper analgesic strategy is of high significance. Although the question of whether morphine causes any harm to cancer patients remains unanswered, alternative analgesic regimens could be used concomitant to or instead of morphine to limit its potential adverse effects.
morphine; regional; anesthesia; analgesia; cancer; surgery
Long-acting opioid formulations are advocated for maintaining pain control in chronic cancer pain. OROS® hydromorphone is a sustained-release formulation of hydromorphone that requires dosing once daily to maintain therapeutic concentrations. The objective of this study was to demonstrate the clinical equivalence of immediate-release and sustained-release formulations of hydromorphone and morphine for chronic cancer pain.
200 patients with cancer pain (requiring ≤ 540 mg/d of oral morphine) participated in this double-blind, parallel-group trial. Patients were randomized to receive hydromorphone or morphine (immediate-release for 2–9 days, sustained-release for 10–15 days). Efficacy was assessed with the Brief Pain Inventory (BPI), investigator and patient global evaluations, Eastern Cooperative Oncology Group performance status, and the Mini-Mental State Examination. The primary endpoint was the 'worst pain in the past 24 hours' item of the BPI, in both the immediate-release and sustained-release study phases, with treatments deemed equivalent if the 95% confidence intervals (CI) of the between-group differences at endpoint were between -1.5 and 1.5. No equivalence limits were defined for secondary endpoints.
Least-squares mean differences (95% CI) between groups were 0.2 (-0.4, 0.9) in the immediate-release phase and -0.8 (-1.6, -0.01) in the sustained-release phase (intent-to-treat population), indicating that the immediate-release formulations met the pre-specified equivalence criteria, but that the lower limit of the 95% CI (-1.6) was outside the boundary (-1.5) for the sustained-release formulations. BPI 'pain now PM' was significantly lower with OROS® hydromorphone compared with controlled-release morphine (least-squares mean difference [95% CI], -0.77 [-1.49, -0.05]; p = 0.0372). Scores for other secondary efficacy variables were similar between the two sustained-release treatments. At endpoint, > 70% of investigators and patients rated both treatments as good to excellent. The safety profiles of hydromorphone and morphine were similar and typical of opioid analgesics.
Equivalence was demonstrated for immediate-release formulations of hydromorphone and morphine, but not for the sustained-release formulations of OROS® hydromorphone and controlled-release morphine. The direction of the mean difference between the treatments (-0.8) and the out-of-range lower limit of the 95% CI (-1.6) were in favor of OROS® hydromorphone.
According to the three step-ladder analgesics in patients with cancer pain, adjuvant drugs are required for pain relief according to the pain character and also to reduce side effects of opioids. Pain clinicians sometimes want to decide to jump directly from naive and mild opioid to transdermal therapeutic system (TTS) fentanyl with less side effects. We investigated the safety, efficacy, and satisfaction of the patients of TTS fentanyl converting from opioid-naive and mild-opioid with adjuvant drug medications in related to dose cascade of TTS fentanyl. Both opioid-naive (n=3) and opioid-using (n=34) patients started with TTS fentanyl in the lowest available delivery rate (25 microg/hr) with rescue medication. A numeric rating scale (NRS, from 0=no pain to 10=worst pain imaginable), satisfaction of the patients with the transdermal therapy and side effects were recorded everyday during 29 days. Average reductions of NRS scores were 1.79 and 2.77, and the mean doses were 35.14 and 44.12 microg/hr on the 15th and 29th day, respectively. Reported level of satisfaction with the transdermal patch and generalized pain management were 'completely satisfied' and 'satisfied'. Frequent side effects were nausea, vomiting, and constipation. In conclusion, initial application of TTS fentanyl with proper adjuvant medications is effective, safe, and well tolerated.
Morphine has been used for many years to relieve cancer pain. Oral morphine (in either immediate release or modified release form) remains the analgesic of choice for moderate or severe cancer pain. The dose of oral morphine is titrated up to achieve adequate relief from pain with minimal side effects. Antidepressant and anticonvulsant drugs, when used in addition to conventional analgesics, give excellent relief from cancer pain. Most cancer pain responds to pharmacological measures with oral morphine but some pain like neuropathic and bony pain, pain in children and elderly age group, and advanced malignancy pain are very difficult to treat. Here, we report the management of a similar patient of severe cancer pain and the difficulty that we came across during dose titration of oral morphine and adjuvant analgesic.
Adjuvant analgesic; Cancer pain; Dose titration; Oral morphine
Gastric cancer (GC) is the fourth most common cancer and the second most common cause of cancer death world-wide after lung cancer. It is a multifactorial disease with the involvement of both genetic and environmental risk factors. Genetic variation in genes encoding cytokines and their receptors, determine the intensity of the inflammatory response, which may contribute to individual differences in severity of outcome of the disease. Tumor necrosis factor alpha (TNF-α) is a potent pro-inflammatory cytokine and acid inhibitor. A bi allelic G to A polymorphism at -308 upstream from the transcription initiation site of the promoter is associated with elevated TNF levels. The present study is aimed at evaluating the role of TNF-α-308 (G → A) gene polymorphism and susceptibility to GC.
Subjects and Methods:
A case-control study was carried out in 114 GC patients and 229 healthy control subjects. TNF-α genotyping at position-308 (G → A) was carried out by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) method followed by agarose gel electrophoresis.
The distribution of TNF-α genotypes at -308 (G → A) were GG 28.07%, GA 66.67% and AA 5.26% in GC patients and GG 33.19%, GA 55.89% and AA 10.92% in control subjects. The frequencies of alleles G and A were 0.614 and 0.386 in GC patients and 0.611 and 0.389 in control subjects respectively.
The study showed no significant difference in the distribution of genotype and allelic frequencies between GC patients and control subject.
Gastric cancer; Helicobacter pylori; promoter polymorphism; tumor necrosis factor alpha
Interindividual variability in pain perception and analgesic response is a major problem in perioperative practice. Adult studies suggest pain management is influenced by patient’s race. The objective of this study is to evaluate the influence of race on perioperative pain treatment in children.
Prospective observational study evaluating effect of race on analgesia and opioid related adverse effects after tonsillectomy in African American and Caucasian children. A sample of 194 healthy children between 6 and 15 years of age were included. Race was self-identified by parents. All participants received standard perioperative care with a standard anesthetic and an intraoperative dose of morphine. Analgesia outcomes included maximum postoperative pain scores, postoperative opioid requirement, and analgesic interventions. Safety outcomes included incidences of opioid related adverse effects.
African American children experienced significantly more postoperative pain than Caucasian children as measured by postoperative opioid requirement (P = .0011), maximum postoperative pain scores (P < .0001), and analgesic interventions (P < .0001) in the recovery room. Although Caucasian children received relatively less opioids perioperatively, they had significantly higher opioid related adverse effects (P = .039). African American children with obstructive sleep apnea were more likely to have prolonged post anesthesia recovery unit stay due to inadequate pain control.
After similar uses of intraoperative morphine for tonsillectomy, there was an unequal burden of increased pain in African American children and increased opioid adverse effects in Caucasian children in the recovery room. Though Caucasian children received relatively less opioids perioperatively, they had higher incidences of opioid related adverse effects than African American children.
pain management; pain response; pain sensitivity; race; safety
Morphine consumption can vary widely between individuals even for identical surgical procedures. As mu-opioid receptor (OPRM1) is known to modulate pain perception and mediate the analgesic effects of opioid compounds in the central nervous system, we examined the influence of two OPRM polymorphisms on acute post-operative pain and morphine usage in women undergoing elective caesarean delivery.
Data on self-reported pain scores and amount of total morphine use according to patient-controlled analgesia were collected from 994 women from the three main ethnic groups in Singapore. We found statistically significant association of the OPRM 118A>G with self-administered morphine during the first 24-hour postoperative period both in terms of total morphine (p = 1.7 × 10-5) and weight-adjusted morphine (p = 6.6 × 10-5). There was also significant association of this OPRM variant and time-averaged self-rated pain scores (p = 0.024). OPRM 118G homozygotes used more morphine and reported higher pain scores than 118A carriers. Other factors which influenced pain score and morphine usage include ethnicity, age and paying class.
Our results suggest that ethnicity and OPRM 118A>G genotype are independent and significant contributors to variation in pain perception and postoperative morphine use in patients undergoing cesarean delivery.
Intrathecal opioid administration has been used widely in patients suffering from severe cancer pain that is not managed with conventional modalities. However, the potential serious neurological complications from the procedure and the side effects of intrathecal opioids have made many clinicians reluctant to employ continuous intrathecal analgesia as a first-line therapeutic option despite its dramatic effect on intractable pain. We retrospectively investigated the efficacy, side effects, and complications of intrathecal morphine administration through intrathecal catheters connected to a subcutaneous injection port (ICSP) in 22 Korean terminal cancer patients with successful intrathecal morphine trials.
Patient demographic data, the duration of intrathecal opioid administration, preoperative numerical pain rating scales (NRS) and doses of systemic opioids, side effects and complications related to intrathecal opioids and the procedure, and the numerical pain rating scales and doses of intrathecal and systemic opioids on the 1st, 3rd, 7th and 30th postoperative days were determined from medical records.
Intrathecal morphine administration for 46.0 ± 61.3 days significantly reduced NRS from baseline on all the postoperative days. A significant increase in intrathecal opioids with a nonsignificant decrease in systemic opioids was observed on the 7th and 30th postoperative days compared to the 1st postoperative day. The most common side effects of intrathecal opioids were nausea/vomiting (31.8%) and urinary retention (38.9%), which were managed with conservative therapies.
Intrathecal morphine administration using ICSP provided immediate and beneficial effects on pain scores with tolerable side effects in terminal cancer patients.
cancer pain; complications; efficacy; intrathecal morphine; side effects
Metastatic bone cancer causes severe pain that is primarily treated with opioids. A model of bone cancer pain in which the progression of cancer pain and bone destruction is tightly controlled was used to evaluate the effects of sustained morphine treatment. In cancer-treated mice, morphine enhanced, rather than diminished, spontaneous, and evoked pain; these effects were dose-dependent and naloxone-sensitive. SP and CGRP positive DRG cells did not differ between sarcoma or control mice, but were increased following morphine in both groups. Morphine increased ATF-3 expression only in DRG cells of sarcoma mice. Morphine did not alter tumor growth in vitro or tumor burden in vivo but accelerated sarcoma-induced bone destruction and doubled the incidence of spontaneous fracture in a dose- and naloxone-sensitive manner. Morphine increased osteoclast activity and upregulated IL-1β within the femurs of sarcoma-treated mice suggesting enhancement of sarcoma-induced osteolysis. These results indicate that sustained morphine increases pain, osteolysis, bone loss, and spontaneous fracture, as well as markers of neuronal damage in DRG cells and expression of pro-inflammatory cytokines. Morphine treatment may result in “add-on” mechanisms of pain beyond those engaged by sarcoma alone. While it is not known whether the present findings in this model of osteolytic sarcoma will generalize to other cancers or opioids, the data suggest a need for increased understanding of neurobiological consequences of prolonged opioid exposure which may allow improvements in the use of opiates in the effective management of cancer pain.
Cancer pain; Opioid hyperalgesia; Cancer; Osteoclast; IL-1; Opiate receptors
Opioid analgesics are essential in the treatment of moderate to severe cancer-related pain. Opioids are also recognized as important in the management of other severe, persistent refractory painful conditions, such as sickle cell disease and arthritis. In the clinical practice of pain management, stable opioid dosing generally depends on achieving maximal analgesia with tolerable side effects typical of opioid analgesics. There is a wide interindividual variability of responsiveness to exogenous opioids both in terms of analgesic efficacy and side effects. Optimizing pain management for the individual patient may require sequential trials of opioid medications until the regimen with the most favorable therapeutic ratio of efficacy to side effects is determined.
analgesics; opioid; hydromorphone; OROS®; extended-release
Spinal proinflammatory cytokines are powerful pain-enhancing signals that contribute to pain following peripheral nerve injury (neuropathic pain). Recently, one proinflammatory cytokine, interleukin-1, was also implicated in the loss of analgesia upon repeated morphine exposure (tolerance). In contrast to prior literature, we demonstrate that the action of several spinal proinflammatory cytokines oppose systemic and intrathecal opioid analgesia, causing reduced pain suppression. In vitro morphine exposure of lumbar dorsal spinal cord caused significant increases in proinflammatory cytokine and chemokine release. Opposition of analgesia by proinflammatory cytokines is rapid, occurring ≤5 minutes after intrathecal (perispinal) opioid administration. We document that opposition of analgesia by proinflammatory cytokines cannot be accounted for by an alteration in spinal morphine concentrations. The acute anti-analgesic effects of proinflammatory cytokines occur in a p38 mitogen-activated protein kinase and nitric oxide dependent fashion. Chronic intrathecal morphine or methadone significantly increased spinal glial activation (toll-like receptor 4 mRNA and protein) and the expression of multiple chemokines and cytokines, combined with development of analgesic tolerance and pain enhancement (hyperalgesia, allodynia). Statistical analysis demonstrated that a cluster of cytokines and chemokines was linked with pain-related behavioral changes. Moreover, blockade of spinal proinflammatory cytokines during a stringent morphine regimen previously associated with altered neuronal function also attenuated enhanced pain, supportive that proinflammatory cytokines are importantly involved in tolerance induced by such regimens. These data implicate multiple opioid-induced spinal proinflammatory cytokines in opposing both acute and chronic opioid analgesia, and provide a novel mechanism for the opposition of acute opioid analgesia.
proinflammatory cytokine; chemokine; morphine; tolerance; glia; microglia; p38 MAP kinase; nitric oxide; toll like receptor-4
Opioid analgesics have proven efficacy in the short-term management of chronic cancer pain, but data on their long-term use is more limited. OROS® hydromorphone is a controlled-release formulation of oral hydromorphone that may be particularly well suited to long-term management of chronic cancer pain because it provides stable plasma concentrations and consistent analgesia with convenient once-daily dosing. The objective of this study (DO-118X) was to characterise the pain control achieved with long-term repeated dosing of OROS® hydromorphone in patients with chronic cancer pain.
In this multicentre, phase III, open-label, single treatment, 1-year extension study, OROS® hydromorphone was administered to 68 patients with moderate-to-severe chronic cancer pain, who had successfully completed a short-term equivalence study, and whose pain was controlled with a stable dose of medication (≥ 8 mg OROS® hydromorphone or equivalent controlled-release morphine). Patients were started on the dose of OROS® hydromorphone equivalent to the opioid dose on which they achieved dose-stable pain control in the equivalence study; dose adjustments were made as necessary and breakthrough pain medication was permitted. Efficacy was assessed with the Brief Pain Inventory (BPI) and patient and investigator global evaluations of treatment effectiveness. No formal statistical analysis was done.
The mean (standard deviation) duration of exposure to study medication was 139 (129.9) days and the mean (standard deviation) average daily consumption of OROS® hydromorphone was 43.7 (28.14) mg/day. All scores were maintained at a mild to moderate severity throughout the study; however, BPI scores for pain at its worst, pain at its least, pain on average, pain right now, and pain relief were slightly worsened at end point compared with baseline. Mean BPI pain interference with daily activities and patient and investigator global evaluation scores also remained generally stable. Treatment effectiveness was rated as fair to good throughout the study. The most frequently reported adverse events were nausea (n = 24, 35.3%), constipation (n = 22, 32.4%), and vomiting (n = 15, 22.1%).
The results of this extension study suggest that long-term repeated dosing with once-daily OROS® hydromorphone can be beneficial in the continuing management of persistent, moderate-to-severe cancer pain.
Breakthrough pain is defined as the transient exacerbation of pain occurring in a patient with otherwise stable, persistent pain. It is estimated to affect over 50% of patients, particularly those with moderate to severe background pain. Breakthrough pain is one of the most difficult pain syndromes to treat. There are several types of breakthrough cancer pain: incidental type involves flares of pain associated with movement or activity; idiopathic type is transitory pain unrelated to a specific activity; and in end-of-dose failure pain occurs when blood levels of medications fall below an analgesic threshold at the end of a dosing interval. Persistent and breakthrough pain are distinct components of cancer pain and require separate management. Successful management of breakthrough pain may require a combination of pharmacological and non-pharmacological treatment strategies. Supplemental analgesia, known as rescue medication, is a common pharmacological treatment option. Breakthrough pain is treated with supplemental short-acting opioid use, as needed, e.g. short-acting morphine, intranasal fentanyl and buccal tablets of fentanyl.
cancer pain; breakthrough pain; breakthrough pain management; neuropathic pain
Opioids are considered a “gold standard” in clinical practice for the treatment of postoperative pain. The spinal administration of an opioid drug does not guarantee selective action and segmental analgesia in the spine. Evidence from experimental studies in animals indicates that bioavailability in the spinal cord biophase is negatively correlated with liposolubility, and is higher for hydrophilic opioids, such as morphine, than lipophilic opioids, such as fentanyl, sufentanil and alfentanil.
Epidural morphine sulphate has proven analgesic efficacy and superiority over systemically administered morphine for improving postoperative pain. However, pain relief after a single epidural injection of morphine could last less than 24 hours. Techniques used to administered and prolong opioid epidural analgesia, can be costly and inconvenient. Moreover, complications can arise from indwelling epidural catheterization, particularly in patients receiving anticoagulants. Clinical trials have shown that epidural morphine in the form of extended-release liposome injections (EREM) gives good analgesia for a period of 48 hours, with no need for epidural catheterisation. Intrathecal morphine produces intense analgesia for up to 24 hours with a single shot, and clinical recommendation is to choose the minimum effective dose and do not exceed 300 μg to prevent the delay respiratory depression.
Cancer pain is multifactorial and complex. The impact of cancer pain is devastating, with increased morbidity and poor quality of life, if not treated adequately. Cancer pain management is a challenging task both due to disease process as well as a consequence of treatment-related side-effects. Optimization of analgesia with oral opioids, adjuvant analgesics, and advanced pain management techniques is the key to success for cancer pain. Early access of oral opioid and interventional pain management techniques can overcome the barriers of cancer pain, with improved quality of life. With timely and proper anticancer therapy, opioids, nerve blocks, and other non-invasive techniques like psychosocial care, satisfactory pain relief can be achieved in most of the patients. Although the WHO Analgesic Ladder is effective for more than 80% cancer pain, addition of appropriate adjuvant drugs along with early intervention is needed for improved Quality of Life. Effective cancer pain treatment requires a holistic approach with timely assessment, measurement of pain, pathophysiology involved in causing particular type of pain, and understanding of drugs to relieve pain with timely inclusion of intervention. Careful evaluation of psychosocial and mental components with good communication is necessary. Barriers to cancer pain management should be overcome with an interdisciplinary approach aiming to provide adequate analgesia with minimal side-effects. Management of cancer pain should comprise not only a physical component but also psychosocial and mental components and social need of the patient. With risk–benefit analysis, interventional techniques should be included in an early stage of pain treatment. This article summarizes the need for early and effective pain management strategies, awareness regarding pain control, and barriers of cancer pain.
Basic issues; Cancer pain; Oral morphine
The analgesia produced by combinations of low-dose naloxone with pentazocine or morphine was studied in 105 patients with moderately severe postoperative pain after standardized surgery for removal of impacted third molars. Pain intensity was quantified using a visual-analogue scale. To eliminate the release of endogenous opioids produced by the placebo component of open drug administration, all injections were made by a preprogrammed infusion pump. The analgesia produced by pentazocine, an agonist-antagonist opiate-analgesic acting predominantly at the kappa opiate receptor, was potentiated by low-dose naloxone, whereas the analgesia produced by morphine, a mu-agonist, was attenuated by low-dose naloxone. To evaluate whether similar potentiation would be present in an animal model, and specifically, in the absence of diazepam, which patients receive, we performed an analogous experiment in rats in which nociceptive threshold was determined using the Randall-Selitto paw-withdrawal test. The results were completely analogous to the clinical results: pentazocine analgesia was potentiated by low-dose naloxone, whereas morphine analgesia was attenuated by low-dose naloxone. These data demonstrate a novel interaction between opiates, and suggest a rationale for opiate combinations to produce potent analgesia with fewer autonomic side effects and less abuse potential than presently available analgesics.
Cancer pain and chronic non-malignant pain can be difficult to manage and may not respond satisfactorily to standard analgesics. Sequential empiric analgesic trials are usually done to manage individual patients. Experimental human pain models have helped to clarify mechanisms of opioid and adjuvant analgesic actions. Combinations of opioids and adjuvant analgesics better relieve pain than either opioids or adjuvant analgesics alone, as demonstrated in randomized controlled trials. The analgesic activity of antidepressants is largely dependent upon norepinephrine reuptake and activation of alpha 2 adrenergic receptors. Corticosteroids reduce postoperative orthopedic incident pain, which may allow patients to ambulate earlier and with less pain. Spinal corticosteroids reduce lower hemibody pain. Gabapentinoids as single high doses reduce postoperative pain and certain acute pain syndromes. Individuals who experience flares of pain while on spinal opioids benefit from intrathecal boluses of levobupivicaine or sublingual ketamine. Interventional approaches to pain management are often necessary due to the limitations of systemic analgesics. Electronics stimulators (peripheral, spinal and motor cortex) improve difficult to manage chronic pain syndromes. Pulsed radiofrequency reduces pain without tissue damage, which could be an advantage over chemical or radiofrequency neurotomy. Botulinum toxin A reduces focal neuropathic pain that is durable. Interventional related successes in relieving pain are operator dependent. Most reported benefits of systemic and regional analgesics and interventional approaches to pain relief are not based on randomized trials and are subject to selection bias, sampling error, and placebo responses, which may over-inflate reported benefits. Randomized controlled trials are needed to confirm reported benefits.
The management of postoperative pain is a key to patient early recovery, in particular, where the surgery was performed to benefit another human being. In recent years it has been recognized that multimodal analgesic methods are superior for postoperative pain relief. It is also imperative to remember that inadequately managed acute postoperative pain opens the doorway to possible suffering from chronic postoperative pain later. Although the laparoscopic donor nephrectomy has reduced the disincentives associated with open surgery, still significant percentage of donors suffers from postoperative pain. In the UK, patient-controlled analgesic system (PCAS) using morphine for postoperative pain relief is being used in majority of the transplant centres. Though opioids provide good analgesia, they are far from being an ideal analgesic due to their adverse effects. This paper pragmatically looks in depth on different modalities of pain management in patients undergoing laparoscopic live donor nephrectomy.
Standard therapy (ST) for postoperative pain after knee and hip replacement at the Hamilton Health Sciences Henderson Hospital consists of epidural analgesia or patient-controlled analgesia for the first 48 hours, followed by oral or parenteral analgesics, or both, on an as-needed basis. We compared the efficacy and safety of scheduled controlled-release (CR) oxycodone hydrochloride (OxyContin; Purdue Pharma, Pickering, Ont.) and ST for postoperative pain 48 hours after primary knee and hip replacement.
In 2 separate 3-week studies of similar design, pain intensity, pain relief, length of hospital stay, analgesic use and side effects of CR oxycodone (n = 70) and ST (n = 101) were evaluated. In the CR oxycodone trial, a dose de-escalation protocol was used.
At the time of discharge from hospital, patients in the CR oxycodone group recorded lower mean (and standard deviation) pain intensity scores than the ST group (20.2 [17.9] v. 27.7 [21.5] mm on a 100-mm visual analogue scale; p = 0.021). Length of hospital stay was 5.5 and 6.4 days for the CR oxycodone and ST groups respectively (p < 0.001). CR oxycodone patients used less opioid (morphine equivalent) while in hospital than ST patients (p < 0.001), and the average number of daily administrations of analgesics in hospital was 2.1 and 3.5 for CR oxycodone and ST patients respectively (p < 0.001). ST patients reported more nausea and vomiting, pruritus and fever than the CR oxycodone patients, but less somnolence, constipation, dizziness, confusion and tachycardia.
CR oxycodone every 12 hours is as effective as ST in treating postoperative pain but length of hospital stay was shorter and analgesic administration in the hospital was used less frequently, providing potential hospital cost savings and reduced use of health care resources.
Patients with moderate to severe malignancy-related pain frequently require the use of opioid pharmacotherapy. Unfortunately, many cancer patients continue to be prescribed subtherapeutic doses of pain medications resulting in undo suffering and diminished quality of life. The choice of analgesic pharmacotherapy should be individualized and based on the intensity and etiology of pain reported by the patient. Health care providers must be able to readily quantify the relative analgesic potency when converting from one opioid to another or from one route of administration to another. Transdermal fentanyl is effective and well tolerated pharmacotherapy for the cancer pain patients. However, clinicians need to be cognizant that the U.S./U.K. manufacturer's recommendations for equilalagesic dosing of transdermal fentanyl may result in initial doses that produce subtherapeutic levels and unrelieved pain in some patients. A more aggressive dosing algorithm for transdermal fentanyl using a 2:1 (mg/day of oral morphine: mcg/hr of transdermal fentanyl) conversion ratio that considers both a review of the literature and clinical experience should help clinicians individualize cancer pain pharmacotherapy. Transdermal buprenorphine is now being prescribed in Europe and Australia for chronic and cancer pain management. Buprenorphine's mixed agonist/antagonist activity, dosage ceiling, and high affinity to the opiate receptor limits its use to those patients who do not already require large daily doses of opioids. Thus, buprenorphine may not be an appropriate medication for some patients with advanced unremitting cancer pain.