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1.  Genetic and Non-Genetic Covariates of Pain Severity in Patients with Adenocarcinoma of the Pancreas: Assessing the Influence of Cytokine Genes 
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.
doi:10.1016/j.jpainsymman.2009.04.019
PMCID: PMC2795073  PMID: 19692203
Pain; genes; cytokines; epidemiology; cancer; analgesia; molecular epidemiology
2.  The role of inflammation gene polymorphisms on pain severity in lung cancer patients 
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.
doi:10.1158/1055-9965.EPI-09-0426
PMCID: PMC2759856  PMID: 19773451
Pain; Genes; Inflammation; Epidemiology; Cancer
3.  Management of breakthrough pain in children with cancer 
Journal of Pain Research  2014;7:117-123.
Breakthrough pain in children with cancer is an exacerbation of severe pain that occurs over a background of otherwise controlled pain. There are no randomized controlled trials in the management of breakthrough pain in children with cancer, and limited data and considerable experience indicate that breakthrough pain in this pediatric patient group is common, underassessed, and undertreated. An ideal therapeutic agent would be rapid in onset, have a relatively short duration, and would be easy to administer. A less effective pharmacologic strategy would be increasing a patient’s dose of scheduled opioids, because this may increase the risk of oversedation. The most common and effective strategy seems to be multimodal analgesia that includes an immediate-release opioid (eg, morphine, fentanyl, hydromorphone, or diamorphine) administered intravenously by a patient-controlled analgesia pump, ensuring an onset of analgesic action within minutes. Intranasal fentanyl (or hydromorphone) may be an alternative, but no pediatric data have been published yet for commercially available fentanyl transmucosal application systems (ie, sublingual tablets/spray, buccal lozenge/tablet/film, and nasal spray), and these products cannot yet be recommended for use with children with cancer and breakthrough pain. The aim of this paper was to emphasize the dearth of available information on treatment of breakthrough pain in pediatric cancer patients, to describe the treatment protocols we currently recommend based on clinical experience, and to suggest future research on this very important and under-researched topic.
doi:10.2147/JPR.S58862
PMCID: PMC3953108  PMID: 24639603
pediatric; cancer; breakthrough pain; opioid; adjuvant analgesia; integrative medicine
4.  Efficacy of Epidural Analgesia in Patients with Cancer Pain: A Retrospective Observational Study 
Yonsei Medical Journal  2012;53(3):649-653.
Purpose
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.
Results
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).
Conclusion
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.
doi:10.3349/ymj.2012.53.3.649
PMCID: PMC3343439  PMID: 22477012
Bupivacaine; cancer pain; epidural analgesia; morphine
5.  A Subanalgesic Dose of Morphine Eliminates Nalbuphine Anti-analgesia in Postoperative Pain 
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.
Perspective
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.
doi:10.1016/j.jpain.2007.11.011
PMCID: PMC2364600  PMID: 18201935
kappa opioid; sexual dimorphism; analgesia; gender
6.  Role of Tumor Necrosis Factor-α -308 G/A Promoter Polymorphism in Gastric Cancer 
Background/Aim:
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.
Results:
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.
Conclusion:
The study showed no significant difference in the distribution of genotype and allelic frequencies between GC patients and control subject.
doi:10.4103/1319-3767.114513
PMCID: PMC3745661  PMID: 23828749
Gastric cancer; Helicobacter pylori; promoter polymorphism; tumor necrosis factor alpha
7.  Review of oral oxymorphone in the management of pain 
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.
PMCID: PMC2621383  PMID: 19209260
chronic pain; oxymorphone; opioids; extended-release; sustained-release; cancer pain
8.  A randomized, double-blind comparison of OROS® hydromorphone and controlled-release morphine for the control of chronic cancer pain 
BMC Palliative Care  2008;7:17.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
Trial registration
ClinicalTrials.gov: NCT0041054
doi:10.1186/1472-684X-7-17
PMCID: PMC2644667  PMID: 18976472
9.  Morphine Use in Cancer Surgery 
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.
doi:10.3389/fphar.2011.00046
PMCID: PMC3151591  PMID: 21852973
morphine; regional; anesthesia; analgesia; cancer; surgery
10.  Effect of Intravenous Patient Controlled Ketamine Analgesiaon Postoperative Pain in Opium Abusers 
Background:
Acutepostoperative pain is among the worst experience that patient scan undergo, and many analgesics have been used to suppress it; especially in chronic opium abusers. Ketamine is an N-methyl-D-aspartate antagonist analgesic, having both anesthetic and analgesic properties, which are not affected to the same extent in chronic opium abusers.
Objectives:
In this study, we assessed the analgesic effects of ketamine added to morphine as a patient-controlled analgesia method for acute pain management, compared with a placebo, inchronic maleopium abusers.
Patients and Methods:
After institutional review board approval for ethical considerations, a randomized double-blinded placebo controlled clinical trial was conducted. A total of 140 male patients aged 18-65 years, undergoing orthopedic surgery, were entered into the study after matching inclusion and exclusion criteria. All patients received the same anesthesia method; while the first group received ketamine (1mg/mL) and morphine (0.5 mg/mL) as a patient-controlled analgesia (70 patients), the second group received morphine (0.5 mg/mL) plus normal saline (70 patients). P value less than 0.05 was considered statistically significant.
Results:
The ketamine and morphine group of patients experienced less postoperative pain and required less postoperative rescue analgesia. However, the unwanted postoperative side effects were nearly the same; although increased levels of postoperative nausea and vomiting were observed in the ketamine and morphine group
Conclusions:
This study demonstrated improved analgesic effects after using intravenous patient controlled analgesia with ketamine on postoperative pain in opium abusers.
doi:10.5812/aapm.14129
PMCID: PMC3961031  PMID: 24701419
Ketamine; Acute Pain; Opium; Drug Users
11.  Initial dose cascade of TTS fentanyl with proper adjuvant medications in cancer pain. 
Journal of Korean Medical Science  2003;18(5):733-737.
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.
PMCID: PMC3055111  PMID: 14555829
12.  Successful Management of a Difficult Cancer Pain Patient by Appropriate Adjuvant and Morphine Titration 
Indian Journal of Palliative Care  2011;17(2):162-165.
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.
doi:10.4103/0973-1075.84541
PMCID: PMC3183609  PMID: 21976860
Adjuvant analgesic; Cancer pain; Dose titration; Oral morphine
13.  Ethnicity and OPRM variant independently predict pain perception and patient-controlled analgesia usage for post-operative pain 
Molecular Pain  2009;5:32.
Background
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.
Results
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.
Conclusion
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.
doi:10.1186/1744-8069-5-32
PMCID: PMC2709614  PMID: 19545447
14.  Race and Unequal Burden of Perioperative Pain and Opioid Related Adverse Effects in Children 
Pediatrics  2012;129(5):832-838.
BACKGROUND:
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.
METHODS:
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.
RESULTS:
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.
CONCLUSIONS:
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.
doi:10.1542/peds.2011-2607
PMCID: PMC3340593  PMID: 22529273
pain management; pain response; pain sensitivity; race; safety
15.  Analgesic effects of adding lidocaine to morphine pumps after orthopedic surgeries 
Background:
Opiate is used in patient-controlled intravenous analgesia pumps (PCIA) for controlling pain in post-surgical patients. Other drugs are remarkably added to opioid pumps to enhance quality, lengthen analgesia, and reduce side effects. Lidocaine, a local anesthetic which inhibits sodium channels, has anesthetic and analgesic effects when injected locally or intravenously. The objective of this study is to evaluate the analgesic effects of adding lidocaine 1% to different doses of morphine via IV pump to patient-controlled analgesia (PCA) after orthopedic surgeries.
Materials and Methods:
In a randomized clinical trial, 60 patients who had undergone orthopedic surgery of lower extremities were divided into three equal groups to control postoperative pain. Intravenous pump with 5 ml/h flow rate was used as the analgesic method. The solution consisted of lidocaine 1% plus 20 mg morphine for the first group, lidocaine 1% plus 10 mg morphine for the second group, and only 20 mg morphine for the third group (control group). Patients were checked every 12 h, and Visual Analog Scale (VAS), extra opioid doses, nausea/vomiting, and sedation scale were examined.
Results:
Pain score was lower in the first group compared to the other two groups. Mean VAS was 2.15 ± 0.2, 2.75 ± 0.2, and 2 ± 0.25 on the first day and 1.88 ± 0.1, 2.74 ± 0.3, and 2.40 ± 0.3 on the second day, respectively, in the three groups and the difference was statistically significant (P < 0.01 and <0.05, respectively). Also, 10% of patients in the first group needed extra opioid doses, while this figure was 30% in the second group and 25% in the third group (P < 0.01). Nausea/vomiting and sedation scores were not statistically different among the three groups.
Conclusion:
Compared to lidocaine 1% plus 10 mg morphine or 20 mg morphine alone in PCIA, adding lidocaine 1% to 20 mg morphine decreases the pain score and opioid dose after orthopedic surgeries without having side effects.
PMCID: PMC3999597  PMID: 24778665
Lidocaine; morphine; patient-controlled analgesia
16.  Frequency, Outcome, and Predictors of Success Within 6 Weeks of an Opioid Rotation Among Outpatients with Cancer Receiving Strong Opioids 
The Oncologist  2012;18(2):212-220.
This study determined the frequency, indications, outcomes, and predictors of successful opioid rotation in outpatients with cancer who were receiving strong opioids.
Learning Objectives
Determine the frequency, indications, and outcomes of opioid rotation in cancer outpatients.Describe the predictors of successful opioid rotation.
Background.
Opioid rotation is used to treat uncontrolled pain and/or opioid-related adverse effects. Our aim was to determine the frequency, indications, outcomes, and predictors of successful opioid rotation in outpatients with cancer.
Methods.
Medical records of consecutive outpatients with cancer who received strong opioids and returned for follow-up visit within ≤6 weeks to our supportive care center from January to December 2008 were reviewed. Data on patient characteristics, symptoms, opioid use, indications for opioid rotation, outcomes, and morphine equivalent daily dose were collected. Successful opioid rotation was defined as a two-point or 30% reduction in the symptom score or the resolution of opioid-induced neurotoxicity and continuation of the new opioid at follow-up.
Results.
Opioid rotation was performed in 120 of 385 patients (31%). The median patient age was 55 years. There were 6/120 patients with missing data. Of the 114 evaluable patients, 68 (60%) were men, 81 (71%) were white, 27 (24%) had gastrointestinal cancer, and 90 (80%) had advanced-stage disease. The median Eastern Cooperative Oncology Group score was 1 (interquartile range: 1–2) and the median time between opioid rotation and follow-up was 14 days (interquartile range: 7–21 days). The most common indications for opioid rotation were uncontrolled pain (95/114; 83%) and opioid-induced neurotoxicity (13/114; 12%). A total of 35 patients (31%) had partial opioid rotation. The median improvements in pain and symptom distress score were −2 (interquartile range: −4 to 0; p < .001) and −5 (interquartile range: −14 to 7; p = .004), respectively. The morphine equivalent daily dose did not change significantly after opioid rotation (p = .156). A total of 65% of patients (74/114) had successful opioid rotation. There were no clinically significant independent predictors for successful opioid rotation.
Conclusion.
Opioid rotation was conducted in 31% of outpatients with cancer, with a 65% success rate. The most frequent reason for opioid rotation was uncontrolled pain. There were no independent predictors for successful opioid rotation.
doi:10.1634/theoncologist.2012-0269
PMCID: PMC3579606  PMID: 23238913
Pain; Opioid rotation; Outpatient; Palliative care; Opioid-induced neurotoxicity
17.  Continuous Intrathecal Morphine Administration for Cancer Pain Management Using an Intrathecal Catheter Connected to a Subcutaneous Injection Port: A Retrospective Analysis of 22 Terminal Cancer Patients in Korean Population 
The Korean Journal of Pain  2013;26(1):32-38.
Background
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.
Methods
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.
Results
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.
Conclusions
Intrathecal morphine administration using ICSP provided immediate and beneficial effects on pain scores with tolerable side effects in terminal cancer patients.
doi:10.3344/kjp.2013.26.1.32
PMCID: PMC3546208  PMID: 23342205
cancer pain; complications; efficacy; intrathecal morphine; side effects
18.  Morphine treatment accelerates sarcoma-induced bone pain, bone loss, and spontaneous fracture in a murine model of bone cancer 
Pain  2007;132(1-2):154-168.
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.
doi:10.1016/j.pain.2007.06.026
PMCID: PMC2704581  PMID: 17706870
Cancer pain; Opioid hyperalgesia; Cancer; Osteoclast; IL-1; Opiate receptors
19.  A new extended release formulation (OROS®) of hydromorphone in the management of pain 
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.
PMCID: PMC2697506  PMID: 19436600
analgesics; opioid; hydromorphone; OROS®; extended-release
20.  Analgesic efficacy of continuous femoral nerve block commenced prior to operative fixation of fractured neck of femur 
Background
Peripheral nerve blocks are effective in treating acute pain, thereby minimizing the requirement for opiate analgesics. Fractured neck of femur (FNF) is a common, painful injury. The provision of effective analgesia to this cohort is challenging but an important determinant of their functional outcome. We investigated the analgesic efficacy of continuous femoral nerve block (CFNB) in patients with FNF.
Methods
Following institutional ethical approval and with informed consent, patients awaiting FNF surgery were randomly allocated to receive either standard opiate-based analgesia (Group 1) or a femoral perineural catheter (Group 2). Patients in Group 1 received parenteral morphine as required. Those in Group 2 received a CFNB comprising a bolus of local anaesthetic followed by a continuous infusion of 0.25% bupivacaine. For both Groups, rescue analgesia consisted of intramuscular morphine as required and all patients received paracetamol regularly. Pain was assessed using a visual analogue scale at rest and during passive movement (dynamic pain score) at 30 min following first analgesic intervention and six hourly thereafter for 72 hours. Patient satisfaction with the analgesic regimen received was recorded using verbal rating scores (0-10). The primary outcome measured was dynamic pain score from initial analgesic intervention to 72 hours later.
Results
Of 27 recruited, 24 patients successfully completed the study protocol and underwent per protocol analysis. The intervals from recruitment to the study until surgery were similar in both groups [31.4(17.7) vs 27.5(14.2) h, P = 0.57]. The groups were similar in terms of baseline clinical characteristics. For patients in Group 2, pain scores at rest were less than those reported by patients in Group 1 [9.5(9.4) vs 31(28), P = 0.031]. Dynamic pain scores reported by patients in Group 2 were less at each time point from 30 min up to 54 hours [e.g at 6 h 30.7(23.4) vs 67.0(32.0), P = 0.004]. Cumulative morphine consumption over 72 h was less in Group 2. Patient satisfaction scores were greater in Group 2 [9.4(1.1) vs 7.6(1.8), P = 0.014].
Conclusions
CFNB provides more effective perioperative analgesia than a standard opiate-based regimen for patients undergoing fixation of FNF. It is associated with lesser opiate use and greater patient satisfaction.
doi:10.1186/2047-0525-1-4
PMCID: PMC3886266  PMID: 24764520
Perioperative pain relief; Hip fractured neck of femur; Continuous femoral nerve block
21.  Epidural Infusion of Morphine and Levobupivacaine through a Subcutaneous Port for Cancer Pain Management 
The Korean Journal of Pain  2014;27(2):139-144.
Background
To manage intractable cancer pain, an alternative to systemic analgesics is neuraxial analgesia. In long-term treatment, intrathecal administration could provide a more satisfactory pain relief with lower doses of analgesics and fewer side-effects than that of epidural administration. However, implantable drug delivery systems using intrathecal pumps in Korea are very expensive. Considering cost-effectiveness, we performed epidural analgesia as an alternative to intrathecal analgesia.
Methods
We retrospectively investigated the efficacy, side effects, and complications of epidural morphine and local anesthetic administration through epidural catheters connected to a subcutaneous injection port in 29 Korean terminal cancer patients. Patient demographic data, the duration of epidural administration, preoperative numerical pain rating scales (NRS), side effects and complications related to the epidural catheterization and the drugs, and the numerical pain rating scales on the 1st, 3rd, 7th and 30th postoperative days were determined from the medical records.
Results
The average score for the numerical pain rating scales for the 29 patients decreased from 7 ± 1.0 at baseline to 3.6 ± 1.4 on postoperative day 1 (P < 0.001). A similar decrease in pain intensity was maintained for 30 days (P < 0.001). Nausea and vomiting were the most frequently reported side effects of the epidural analgesia and two patients (6.9%) experienced paresthesia.
Conclusions
Epidural morphine and local anesthetic infusion with a subcutaneous pump seems to have an acceptable risk-benefit ratio and allows a high degree of autonomy to patients with cancer pain.
doi:10.3344/kjp.2014.27.2.139
PMCID: PMC3990822  PMID: 24748942
cancer pain; efficacy; epidural catheter; port; side effects
22.  Use of Oxycodone in Pain Management 
Anesthesiology and Pain Medicine  2012;1(4):262-264.
Oxycodone is widely used to alleviate moderate-to severe acute pain, It is an effective analgesic for many types of pain, and is especially useful for paroxysmal spontaneous pain, steady pain, allodynia associated with postherpetic neuralgia, and it is also increasingly used in the management of cancer-related and chronic pain, oxycodone has been found to improve the quality of life of patients with many types of pain.
In 2011, following chemical and physical manipulation, an extended-release form of oxycodone was developed in order to maintain its rate-controlling mechanism. This new formulation significantly improved analgesia among patients with moderate-to-severe chronic osteoarthritis pain with an adverse event profile similar to that of other opioids. The long-term safety and efficacy of extended-release form of oxycodone in relieving moderate-to-severe chronic pain has been demonstrated. In this study we discussed about different aspects of this drug in managing of various types of pain.
doi:10.5812/aapm.4529
PMCID: PMC4018705  PMID: 24904812
Oxycodone; Pain; Analgesics, Opioid
23.  An open-label, 1-year extension study of the long-term safety and efficacy of once-daily OROS® hydromorphone in patients with chronic cancer pain 
BMC Palliative Care  2009;8:14.
Background
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.
Methods
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.
Results
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%).
Conclusion
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.
doi:10.1186/1472-684X-8-14
PMCID: PMC2753576  PMID: 19754935
24.  Management of breakthrough pain due to cancer 
Contemporary Oncology  2013;16(6):498-501.
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.
doi:10.5114/wo.2012.32481
PMCID: PMC3687475  PMID: 23788935
cancer pain; breakthrough pain; breakthrough pain management; neuropathic pain
25.  Proinflammatory cytokines oppose opioid induced acute and chronic analgesia 
Brain, behavior, and immunity  2008;22(8):1178-1189.
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.
doi:10.1016/j.bbi.2008.05.004
PMCID: PMC2783238  PMID: 18599265
proinflammatory cytokine; chemokine; morphine; tolerance; glia; microglia; p38 MAP kinase; nitric oxide; toll like receptor-4

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