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1.  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.
PMCID: PMC2759856  PMID: 19773451
Pain; Genes; Inflammation; Epidemiology; Cancer
2.  Breathlessness With Pulmonary Metastases: A Multimodal Approach 
Case Study 
Sarah is a 58-year-old breast cancer survivor, social worker, and health-care administrator at a long-term care facility. She lives with her husband and enjoys gardening and reading. She has two grown children and three grandchildren who live approximately 180 miles away.
One morning while showering, Sarah detected a painless quarter-sized lump on her inner thigh. While she thought it was unusual, she felt it would probably go away. One month later, she felt the lump again; she thought that it had grown, so she scheduled a visit with her primary care physician. A CT scan revealed a 6.2-cm soft-tissue mass in the left groin. She was referred to an oncologic surgeon and underwent an excision of the groin mass. Pathology revealed a grade 3 malignant melanoma. She was later tested and found to have BRAF-negative status. Following her recovery from surgery, Sarah was further evaluated with an MRI scan of the brain, which was negative, and a PET scan, which revealed two nodules in the left lung.
As Sarah had attended a cancer support group during her breast cancer treatment in the past, she decided to go back to the group when she learned of her melanoma diagnosis. While the treatment options for her lung lesions included interleukin-2, ipilimumab (Yervoy), temozolomide, dacarbazine, a clinical trial, or radiosurgery, Sarah's oncologist felt that ipilimumab or radiosurgery would be the best course of action. She shared with her support group that she was ambivalent about this decision, as she had experienced profound fatigue and nausea with chemotherapy during her past treatment for breast cancer. She eventually opted to undergo stereotactic radiosurgery.
After the radiosurgery, Sarah was followed every 2 months. She complained of shortness of breath about 2 weeks prior to each follow-up visit. Each time her chest x-ray was normal, and she eventually believed that her breathlessness was anxiety-related. Unfortunately, Sarah’s 1-year follow-up exam revealed a 2 cm × 3 cm mass in her left lung, for which she had a surgical wedge resection. Her complaints of shortness of breath increased following the surgery and occurred most often with anxiety, heat, and gardening activities, especially when she needed to bend over. Sarah also complained of a burning "pins and needles" sensation at the surgical chest wall site that was bothersome and would wake her up at night.
Sarah met with the nurse practitioner in the symptom management clinic to discuss her concerns. Upon physical examination, observable signs of breathlessness were lacking, and oxygen saturation remained stable at 94%, but Sarah rated her breathlessness as 7 on the 0 to 10 Borg scale. The nurse practitioner prescribed duloxetine to help manage the surgical site neuropathic pain and to assist with anxiety, which in turn could possibly improve Sarah’s breathlessness. Several nonpharmacologic modalities for breathlessness were also recommended: using a fan directed toward her face, working in the garden in the early morning when the weather is cooler, gardening in containers that are at eye level to avoid the need to bend down, and performing relaxation exercises with pursed lip breathing to relieve anxiety-provoked breathlessness. One month later, Sarah reported relief of her anxiety; she stated that the fan directed toward her face helped most when she started to feel "air hungry." She rated her breathlessness at 4/10 on the Borg scale.
Sarah’s chest x-rays remained clear for 6 months, but she developed a chronic cough shortly before the 9-month exam. An x-ray revealed several bilateral lung lesions and growth in the area of the previously resected lung nodule. Systemic therapy was recommended, and she underwent two cycles of ipilimumab. Sarah’s cough and breathlessness worsened, she developed colitis, and she decided to stop therapy after the third cycle. In addition, her coughing spells triggered bronchospasms that resulted in severe anxiety, panic attacks, and air hunger. She rated her breathlessness at 10/10 on the Borg scale during these episodes. She found communication difficult due to the cough and began to isolate herself. She continued to attend the support group weekly but had difficulty participating in conversation due to her cough.
Sarah was seen in the symptom management clinic every 2 weeks or more often as needed. No acute distress was present at the beginning of each visit, but when Sarah began to talk about her symptoms and fear of dying, her shortness of breath and anxiety increased. The symptom management nurse practitioner treated the suspected underlying cause of the breathlessness and prescribed oral lorazepam (0.5 to 1 mg every 6 hours) for anxiety and codeine cough syrup for the cough. Opioids were initiated for chest wall pain and to control the breathlessness. Controlled-release oxycodone was started at 10 mg every 12 hours with a breakthrough pain (BTP) dose of 5 mg every 2 hours as needed for breathlessness or pain. Sarah noted improvement in her symptoms and reported a Borg scale rating of 5/10. Oxygen therapy was attempted, but subjective improvement in Sarah’s breathlessness was lacking.
Sarah’s disease progressed to the liver, and she began experiencing more notable signs of breathlessness: nasal flaring, tachycardia, and restlessness. Opioid doses were titrated over the course of 3 months to oxycodone (40 mg every 12 hours) with a BTP dose of 10 to 15 mg every 2 hours as needed, but her breathlessness caused significant distress, which she rated 8/10. The oxycodone was rotated to IV morphine continuous infusion with patient-controlled analgesia (PCA) that was delivered through her implantable port. This combination allowed Sarah to depress the PCA as needed and achieve immediate control of her dyspneic episodes. Oral lorazepam was also continued as needed.
Sarah’s daughter moved home to take care of her mother, and hospice became involved for end-of-life care. As Sarah became less responsive, nurses maintained doses of morphine for control of pain and breathlessness and used a respiratory distress observation scale to assess for breathlessness since Sarah could no longer self-report. A bolus PCA dose of morphine was administered by Sarah’s daughter if her mother appeared to be in distress. Sarah died peacefully in her home without signs of distress.
PMCID: PMC4093448  PMID: 25032021
3.  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.
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.
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.
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.
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.
PMCID: PMC3579606  PMID: 23238913
Pain; Opioid rotation; Outpatient; Palliative care; Opioid-induced neurotoxicity
4.  Effectiveness and Safety of Fentanyl Compared with Morphine for Out-of-Hospital Analgesia 
Fentanyl has several potential advantages for out-of-hospital analgesia, including rapid onset, short duration, and less histamine release.
To compare the effectiveness and safety of fentanyl with that of morphine.
This was a retrospective before-and-after study of a protocol change from morphine to fentanyl in an advanced life support emergency medical services system in January 2007. Charts from nine months prior to the change and for nine months afterward were abstracted by two reviewers using a standardized instrument. The first three months after the change were excluded. Effectiveness was measured by change in pain scores on a 0--10 scale. A priori-defined adverse events included out-of-hospital events: respiratory rate <12 breaths/min, pulse oximetry <92%, systolic blood pressure <90 mmHg, any fall in Glasgow Coma Scale score, nausea or vomiting, intubation, and use of antiemetic agents or naloxone. Emergency department charts were reviewed for initial pain scores and the same adverse events during the first two hours. Events clearly not attributable to the opioid were discounted. The changes in pain scores were also compared adjusting for confounders by multivariable linear regression.
Three hundred fifty-five patients aged 13 to 99 years received morphine during the nine months before the protocol change and 363 received fentanyl following the washout period. Initial pain scores for morphine (8.1) and fentanyl (8.3) were comparable (95% confidence interval [CI] for difference -1.1 to 0.3). Fentanyl patients received a higher equivalent dose of opioid (7.7 mg morphine equivalents for morphine, 9.2 mg for fentanyl, CI for the difference 0.9 to 2.3). The mean decreases in pain score were similar between the drugs (2.9 for morphine, 3.1 for fentanyl, CI for the difference -0.3 to 0.7). With regard to adverse events, 9.9% of the morphine patients and 6.6% of the fentanyl patients experienced an adverse event in the field (CI for the difference -0.8 to 7.3%). The most common event was nausea, with a rate of 7.0% for morphine vs. 3.8% for fentanyl (CI for the difference -0.1% to 6.5%).
Morphine and fentanyl provide similar degrees of out-of-hospital analgesia, although this was achieved with a higher dose of fentanyl. Both medications had low rates of adverse events, which were easily controlled.
PMCID: PMC2924527  PMID: 20199230
analgesia; fentanyl; morphine; analgesics; opioid; prehospital emergency care; emergency medical services
5.  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.
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.
PMCID: PMC2753576  PMID: 19754935
6.  Ready Conversion of Patients with Well-Controlled, Moderate to Severe, Chronic Malignant Tumor–related Pain on Other Opioids to Tapentadol Extended Release 
Clinical Drug Investigation  2014;34(7):501-511.
Background and Objectives
The effectiveness and tolerability of tapentadol extended release (ER), a centrally acting analgesic with μ-opioid receptor agonist and norepinephrine (noradrenaline) reuptake inhibitor activities, have been demonstrated in patients with chronic pain, including those switching directly from prior opioid therapy. The objective of the current study was to evaluate the effectiveness and safety of conversion to oral tapentadol ER (50–250 mg twice daily) from previous around-the-clock strong opioid therapy in patients with moderate to severe, chronic malignant tumor–related cancer pain that was well-controlled.
This randomized, open-label, phase III study, which was conducted in Japan, included a 1- to 2-week screening period (on previous opioid) and an 8-week, open-label treatment period. Eligible patients, who were taking a strong opioid analgesic and had a mean pain intensity score <4 during the 3 days prior to randomization (adequate pain control on previous strong opioid), were randomized (1:1) to receive twice-daily treatment with tapentadol ER (100–500 mg/day) or morphine sustained release (SR; 20–140 mg/day; reference for assay sensitivity). Initial doses were estimated based on the conversion ratio of tapentadol ER:oxycodone:morphine:fentanyl = 10:2:3:0.03. The primary effectiveness endpoint was the proportion of patients who maintained pain control [change from baseline in mean pain intensity (11-point numerical rating scale) less than +1.5 for 3 consecutive days and no more than two doses of rescue medication per day for 3 consecutive days) during the first week of open-label treatment.
In the tapentadol ER group (n = 50), 84.0 % of patients (42/50; 95 % CI, 70.89–92.83) maintained pain control during Week 1. On the Patient Global Impression of Change, 2.1 % (1/48), 2.1 % (1/48), 22.9 % (11/48), and 50.0 % (24/48) of patients in the tapentadol ER group reported that their overall condition was “very much improved,” “much improved,” “minimally improved,” and “not changed,” respectively, at Week 1 compared with 0 %, 10.7 % (3/28), 28.6 % (8/28), and 53.6 % (15/28) reporting these ratings at Week 8. The sensitivity of effectiveness analyses was validated based on results using morphine SR; 98.0 % (49/50; 95 % CI, 89.35–99.95) of patients in the morphine SR group maintained pain control after 1 week of treatment. The overall safety profile was similar to that demonstrated in previous studies; tapentadol ER was associated with a lower incidence of gastrointestinal treatment-emergent adverse events than morphine SR [38.0 % (19/50) vs. 54.0 % (27/50)], including constipation [12.0 % (6/50) vs. 20.0 % (10/50)] and vomiting [6.0 % (3/50) vs. 26.0 % (13/50)].
Overall, results indicate that conversion from previous strong opioids to tapentadol ER (50–250 mg twice daily) was successful and resulted in safe and effective pain control with improved gastrointestinal tolerability versus morphine SR in patients with moderate to severe cancer-related pain that was well-controlled on their previous opioid.
Electronic supplementary material
The online version of this article (doi:10.1007/s40261-014-0204-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4062813  PMID: 24906437
7.  Randomized Clinical Trial of an Intravenous Hydromorphone Titration Protocol versus Usual Care for Management of Acute Pain in Older Emergency Department Patients 
Drugs & aging  2013;30(9):747-754.
Background and Objectives
Opioid titration is an effective strategy for treating pain. However, titration is generally impractical in the busy emergency department (ED) setting. Our objective was to test a rapid, 2-step, hydromorphone titration protocol against usual care in older patients presenting to the ED with acute severe pain.
This was a prospective, randomized clinical trial of patients 65 years of age and older presenting to an adult, urban, academic ED with acute severe pain. The study was registered at (NCT01429285). Patients randomized to the hydromorphone titration protocol initially received 0.5 mg intravenous (IV) hydromorphone. Patients randomized to usual care received any dose of any IV opioid. At 15 minutes, patients in both groups were asked, “Do you want more pain medication?” Patients in the hydromorphone titration group who answered “yes” received a second dose of 0.5 mg IV hydromorphone. Patients in the usual care group who answered “yes” had their treating attending notified, who then could administer any (or no) additional medication. The primary efficacy outcome was satisfactory analgesia defined a priori as the patient declining additional analgesia at least once when asked at 15 or 60 minutes after administration of initial opioid. Dose was calculated in morphine equivalent units (MEU: 1 mg hydromorphone = 7 mg morphine). Need for naloxone to reverse adverse opioid effects was the primary safety outcome.
83.0% of 153 patients in hydromorphone titration group achieved satisfactory analgesia compared to 82.5% of 166 patients in the usual care group (p=0.91). Patients in the hydromorphone titration group received lower mean initial doses of opioids at baseline than patients in UC (3.5 MEU vs. 4.7 MEU respectively, p=<0.001) and lower total opioids through 60 minutes (5.3 MEU vs. 6.0 MEU, p=0.03). No patient needed naloxone.
Low-dose titration of IV hydromorphone in increments of 0.5 mg provides comparable analgesia to usual care with less opioid over 60 minutes.
PMCID: PMC3758665  PMID: 23846749
8.  Efficacy of Epidural Analgesia in Patients with Cancer Pain: A Retrospective Observational Study 
Yonsei Medical Journal  2012;53(3):649-653.
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.
PMCID: PMC3343439  PMID: 22477012
Bupivacaine; cancer pain; epidural analgesia; morphine
9.  Oral Morphine Prescribing Practices in Severe Cancer Pain 
Indian Journal of Palliative Care  2009;15(2):127-131.
Nearly one million cancer patients in India need oral morphine for pain relief. Despite doctors prescribing oral morphine in our center, many cancer patients with severe pain found to be not facilitated with adequate pain relief.
This audit was conducted to look at the “oral morphine prescribing practices for severe cancer pain” at a tertiary care hospital.
Materials and Methods:
Twenty case files of patients, who were admitted with severe cancer pain, and receiving oral morphine were analyzed in pre- and posteducational session. Local standards were set to assess the adequacy of pain relief. Deficiency in achieving analgesia was found in preinterventional audit. A clinical audit was conducted before and after the educational session on oral morphine prescribing. The education for doctors and nurses focused on starting patients on morphine, titration, and administering rescue dose. Then local guidelines on oral morphine prescribing were circulated. And analysis of following factors were done following pre- and posteducational session: Pain intensity at the beginning of treatment, starting dose of morphine, increments in morphine dose, number of rescue doses given, and fall in pain intensity at the end of 1 week. The outcomes were compared with the standards.
Preintervention audit showed that only 50% of patients achieved adequate pain relief. Rescue dose was administered in only 20% of patients. While reaudit following the educational session showed that 80% of patients achieved adequate pain relief and 100% received rescue doses.
Educational sessions have significant impact on improving oral morphine prescribing practice among doctors and nurses. It was found failing to administer regular as well as rescue doses resulted in inadequate pain relief in patients receiving oral morphine.
PMCID: PMC2902113  PMID: 20668591
Cancer pain; Oral morphine; Pain relief; Prescribing practices
10.  Adult Emergency Department Patients with Sickle Cell Pain Crisis: Results from a Quality Improvement Learning Collaborative Model to Improve Analgesic Management 
The aim of this study was to 1) estimate differences in pain management process and patient-reported outcomes, pre- and post-implementation of analgesic protocols for adults with sickle cell disease (SCD); and 2) examine the effects of site and visit frequency on changes in pain scores and time to analgesic.
A multi-center, prospective, longitudinal study enrolled patients from three academic medical centers between October 2007 and September 2009. All ED patients 18 years or older with a chief complaint of a sickle cell pain episode were enrolled. Sites formed a SCD quality improvement team and implemented standard nurse-initiated emergency department (ED) analgesic protocols; outcomes were compared between study periods defined as pre- and post-implementation of protocols. Medical record review was conducted to measure time to administration of initial analgesic, opioids used, route of opioid administration, the change in pain scores from arrival to discharge (negative numbers reflect a decrease in pain scores), and the number of ED visits per individual patient during the study period at each site. On day seven after the ED visit, a follow-up phone interview was conducted. Patients were queried about their ED pain management using a scale from 1-10 (1 = outstanding, 10 = worst). Descriptive statistics are used to report the results. Ordinary least squares regression models were constructed to measure the effect of time period, site, and number of visits per patient on change in pain score.
During the study period, 342 unique patients (57% female, mean age 32 years, SD ±11 years) were enrolled and had a total of 2,934 visits. There was no difference in time to administration of the initial analgesic between study periods. Overall, there was a significant decrease in pain scores from arrival to discharge between the pre- and post-intervention study periods: the average difference in arrival to discharge pain scores (cm) was greater during the post-implementation period than during the per-intervention period (−4.1 vs −3.6, t = 2.6, p < 0.01). Site 1 had significant improvement between study periods (mean difference = −0.87, t = 2.63, p < 0.01; F = 14.3, p < 0.01). Patients with few ED visits (one to six annual visits, mean difference −1.55, t = 2.1, p = 0.04) and those with frequent ED visits (seven to 19 annual visits, mean difference −1.65, t = 3.52, p < 0.01) had a significant decrease in pain scores as compared to patients with very frequent ED visits (>19 visits). There was an overall decrease in the use of morphine sulfate and increase in the use of hydromorphone (x2 = 105.67, p < 0.001) between study periods and a significant increase in the use of oral and subcutaneous routes, with a corresponding decrease in the intravenous route (x2 = 13.67, p < 0.001). There were no statistically significant differences in patient-reported satisfaction with the attempt to manage pain in the ED between study periods (p = 0.54).
While the use of a learning collaborative and implementation of nurse-initiated analgesic protocols was not associated with improvement in time to administration of the initial analgesic, improvements in the decrease in the arrival to discharge pain score, and increased use of hydromorphone and the subcutaneous route, were noted in adults with SCD in the ED.
PMCID: PMC3691105  PMID: 22506947
11.  Oxycodone Controlled Release in Cancer Pain Management 
Oral opioids are the treatment of choice for chronic cancer pain. Morphine is the strong opioid of choice for the treatment of moderate to severe cancer pain according to guidelines from the World Health Organization (WHO). This recommendation by the WHO was derived from availability, familiarity to clinicians, established effectiveness, simplicity of administration, and relative inexpensive cost. It was not based on proven therapeutic superiority over other options. Patients who experience inadequate pain relief or intolerable side effects with one opioid may often be successfully treated with another agent or with the same agent administered by a different route. Opioid rotation, or switching to an alternative opioid, helps some patients achieve better pain control with fewer associated adverse effects. Oxycodone is a μ-opioid receptor specific ligand, with clear agonist properties. It is an active potent opioid, which is in part a κ-receptor agonist. Like morphine and other pure agonists, there is no known ceiling to the analgesic effects of oxycodone. The active metabolites of oxycodone (eg, oxymorphone) could be important in oxycodone-mediated analgesia. The main pharmacokinetic difference between oxycodone and morphine is in oral bioavailability. The bioavailability of oxycodone is >60% and the bioavailability of morphine is 20%. Controlled-release oxycodone is absorbed in a bi-exponential fashion. There is a rapid phase with a mean half-life of 37 min, accounting for 38% of the dose, and a slow phase with a half-life of 6.2 h, which accounts for the residual 62%. Oxycodone elimination is impaired by renal failure because there are both an increased volume of distribution and reduced clearance. A lot of studies prove that the efficacy of controlled-release oxycodone in cancer-pain control is at least the same as morphine, immediate-release oxycodone and hydromorphone. Its toxicity profile seems better than that of morphine. There are actually several illustrations of a lower incidence of side-effects in the central nervous system. It is therefore possible to conclude that oxycodone represents a valid alternative to morphine in the management of moderate to severe cancer pain, also as first-line treatment.
PMCID: PMC1936259  PMID: 18360598
oxycodone; opioids; cancer pain; analgesic; morphine
12.  Retrospective analysis of high-dose intrathecal morphine for analgesia after pelvic surgery 
The effectiveness of intrathecal opioids (ITOs) for postoperative analgesia has been limited by reduced opioid dosing because of opioid-related side effects, most importantly respiratory depression. To overcome these limitations, high-dose intrathecal morphine was combined with a continuous intravenous (IV) postoperative naloxone infusion. The aim of the present chart analysis was to investigate the safety and efficacy of high-dose ITOs combined with IV naloxone compared with IV opioid analgesia alone.
A retrospective chart analysis was performed on 121 female patients requiring major pelvic surgery. Ninety-eight patients received a single injection of high-dose ITOs before administration of typical general anesthesia, followed by an IV naloxone infusion at 5 μg/kg/h started post-ITO and continued for 22 h postoperatively. Twenty-three patients were given IV morphine (IVM) for postoperative analgesia and served as a reference group. Postoperative pain relief, analgesic consumption and ability to ambulate were assessed for 48 h postoperatively. Treatment safety was assessed by monitoring opioid-related side effects and vital signs. Data are presented as mean ± SD.
Mean ITOs given were morphine 1.1±0.2 mg combined with fentanyl 49±6 μg. The mean worst pain visual analogue scale score in the first 12 h postoperatively was 0.2±0.90 in the ITO group versus 4.3±3.0 in the IVM group (P<0.05). On postoperative day 2, the mean worst pain visual analogue scale score was only 1±1.8 in the ITO group versus 4.1±2.6 in the IVM group (P<0.05). Analgesic requirements were reduced in the ITO group. In the first 24 h, the ITO group used 6.8±10.2 morphine equivalents (mg IV) versus 76.1±44.4 in the IVM group (P<0.05). All patients in the ITO group were able to ambulate in the first 12 h postoperatively compared with 17/23 in the IVM group. There was a higher incidence of opioid-related sedation in the IVM group. Other opioid-related side effects were infrequent and minor in both groups.
High-dose ITOs combined with a postoperative IV naloxone infusion provided excellent analgesia for major pelvic surgery. The IV naloxone infusion combined with high-dose ITOs appeared to control opioid side effects without affecting analgesia.
PMCID: PMC3052403  PMID: 21369537
Intrathecal opioids; Morphine; Naloxone; Spinal analgesia
13.  Hemi body irradiation: An economical way of palliation of pain in bone metastasis in advanced cancer 
South Asian Journal of Cancer  2014;3(1):28-32.
The primary aim of this prospective non-randomized study was to evaluate the effect of hemi-body irradiation (HBI) on pain and quality of life in cancer patients with extensive bone metastases. The secondary aim was to evaluate side-effects and cost-effectiveness of the treatment.
Materials and Methods:
Between March 2008 and December 2010, a total of 23 (male = 14, female = 9, median age = 60 years) diagnosed cases of metastatic cancer patients (prostate = 11, breast = 6, and lung = 6) received HBI, which was delivered as lower (n = 7) (dose = 8 Gy), upper (n = 8) (dose = 6 Gy), or sequential HBI (n = 8) with a Telecobalt unit (Theratron 780C). Among them, one lung cancer patient died at 2 months and one prostate cancer patient defaulted after the second follow-up. Thus, 21 patients (male = 13, female = 8, median age = 65 years) (prostatic cancer = 10, breast cancer = 6, and lung cancer = 5) were followed up for a minimum of 6 months. Evaluations were performed before and at 2, 4, 8, 16, and 24 weeks after treatment. Pain evaluation was done by Visual Analogue Scale (VAS), Verbal Rating Scale (VRS), Percentage of Pain Relief (PRR), and Global Pain Score (GPS). Toxicity was assessed by CTC v-3 toxicity scores in the medical record. Assessment of oral morphine consumption was done before and after radiation using paired t-test, and correlation analysis was also done with decrease of morphine consumption and reduction of pain score using statistical analysis.
Response (control of pain) was partial (PR) in 67% and complete (CR) in 22% of patients. For most patients, the pain control lasted throughout the follow-up period (6 months). From 66.66% patients requiring 13 or more Morphine (10 mg) tablets per day prior to HBI, none of the patients required to consume 13 or more Morphine (10 mg) tablets per day following HBI, which was correlated with significant reduction in various pain scores (P < 0.05). One way ANOVA with Dunnett's Multiple Comparison Test (P < 0.05) was significant in VAS score changes, VRS score changes, PPR score changes, and GPS score changes. Along with the decrease in morphine tablets, the Linear Correlation of various scales for pain reduction like VAS, VRS, PPR, and GPS were significant. As such, the quality of life was better due to decreased pain and also, a decrease in the dose of analgesics. Grade 1 and 2 hematological toxicity and grade 1 diarrhea were observed as common side-effects. The average total cost of treatment including hospital stay, medicines, and radiation charges was around INR 400.00.
This study shows that hemibody irradiation is not only an effective modality for palliation of severe bone pain in advanced cancer cases but also economical, involves short hospital stay, with acceptable side-effects, utilizes the simple Telecobalt machine, and is less cumbersome in comparison to other currently available pain palliation methods like oral morphine and radiopharmaceuticals.
PMCID: PMC3961864  PMID: 24665443
Bone metastasis; hemibody irradiation; palliation; pain
14.  Time of Admission, Gender and Age: Challenging Factors in Emergency Renal Colic - A Preliminary Study 
Trauma Monthly  2012;17(3):329-332.
Nephrolithiasis is a relatively common problem and a frequent Emergency Department (ED) diagnosis in patients who present with acute flank/abdominal pain. The pain management in these patients is often challenging.
To investigate the most effective dose of morphine with the least side effects in emergency renal colic patients.
Materials and Methods
150 renal colic patients who experienced a pain level of 4 or greater, based on visual analog scale (VAS) at admission time were included. Pain was scored on a 100 mm VAS (0 = no pain, 100 = the worst pain imagined). When patients arrived at ED, a physician would examine the patients and assessed initial pain score, then filled a questionnaire according to the patient information. Patients were assigned to receive 2.5 mg morphine sulfate intravenously. We monitored patients’ visual analog scale (VAS), and adverse events at different time points (every 15 minutes) for 90 minutes. Additional doses of intravenous morphine (2.5 mg) were administered if the patient still had pain. (Max dose: 10 mg). The cumulative dose of morphine, defined as the total amount of morphine prescribed to each patient during the 90 minutes of the study, was recorded. Patients were not permitted to use any nonsteroidal anti-inflammatory drugs as coadjuvant analgesics during the study period. Subjects with inadequate pain relief at 90 minutes received rescue morphine and were excluded from the study. The primary end point in this study was pain relief at 90 minutes, defined as either VAS<40 or decrease of 50% or more as compared to the initial VAS. The secondary objective was to detect the occurrence of adverse effects at any time points in ED.
The studied patients consisted of 104 men and 46 women with the mean age of 43 ±14 years (range, 18 to 75 years). There was no statistically significant difference between the mean age and gender differences in pain response. Rescue analgesia at 30 minutes were given in 54.5% receiving morphine. The average time to painless was 35 minutes. But there were no statistically significant differences between the mean age and gender differences in pain response (P > 0.05). Older patients responded sooner to morphine than the young. Most of the patients had a pain score of 90 -100 (77.3 %) at the beginning that was reduced to 29.4% during the 30 minutes follow up. During the first hour, we found that 94.7% of the patients had no pain or significant pain reduction and only 2.1% of the patients still had pain.
We conclude that there were no significant differences among the gender, time of admission and side - effects in renal colic patients in response to morphine.
PMCID: PMC3860620  PMID: 24350118
Morphine; Renal Colic; Adverse Effect; Gender
15.  Pre-operative pain sensitivity: A prediction of post-operative outcome in the obstetric population 
Experimental assessments can determine pain threshold and tolerance, which mirror sensitivity to pain. This, in turn, influences the post-operative experience.
The study intended to evaluate whether the pre-operative pressure and electrical pain tests can predict pain and opioid requirement following cesarean delivery.
Settings and Design:
Research was conducted on females scheduled for cesarean section at a tertiary care hospital of the state. Twenty women were enrolled, after obtaining written informed consent.
Materials and Methods:
Pain assessment was performed on the eve of cesarean sections using three devices: PainMatcher; determined electrical pain threshold while the algometers PainTest™ FPN100 (manual) and PainTest™ FPX 25 (digital) evaluated pressure pain threshold and tolerance. Post-operative pain relief included intravenous morphine administered by patient-controlled analgesia, diclofenac (100 mg, every 12 h, rectally, enforced) and paracetamol (1000 mg, every 4-6 h, orally, on patient request). Pain scores were reported on numerical rating scales at specified time intervals.
Statistical Analysis Used:
Correlational and regression statistics were computed using IBM SPSS Statistics 21 software (IBM Corporation, USA).
A significant correlation was observed between morphine requirement and: (1) electrical pain threshold (r = -0.45, P = 0.025), (2) pressure pain threshold (r = -0.41 P = 0.036) and (3) pressure pain tolerance (r = -0.44, P = 0.026) measured by the digital algometer. The parsimonious regression model for morphine requirement consisted of electrical pain threshold (r2= 0.20, P = 0.049). The dose of morphine consumed within 48 h of surgery decreases by 0.9 mg for every unit increment in electrical pain threshold.
The predictive power of pain sensitivity assessments, particularly electrical pain threshold, may portend post-cesarean outcomes, including opioid requirements.
PMCID: PMC3819839  PMID: 24249982
Analgesia; anesthesia; cesarean section; obstetrical; pain threshold; patient-controlled; post-operative pain
16.  Impact of perioperative dexamethasone on postoperative analgesia and side-effects: systematic review and meta-analysis 
BJA: British Journal of Anaesthesia  2012;110(2):191-200.
The analgesic efficacy and adverse effects of a single perioperative dose of dexamethasone are unclear. We performed a systematic review to evaluate the impact of a single i.v. dose of dexamethasone on postoperative pain and explore adverse events associated with this treatment.
MEDLINE, EMBASE, CINAHL, and the Cochrane Register were searched for randomized, controlled studies that compared dexamethasone vs placebo or an antiemetic in adult patients undergoing general anaesthesia and reported pain outcomes.
Forty-five studies involving 5796 patients receiving dexamethasone 1.25–20 mg were included. Patients receiving dexamethasone had lower pain scores at 2 h {mean difference (MD) −0.49 [95% confidence interval (CI): −0.83, −0.15]} and 24 h [MD −0.48 (95% CI: −0.62, −0.35)] after surgery. Dexamethasone-treated patients used less opioids at 2 h [MD −0.87 mg morphine equivalents (95% CI: −1.40 to −0.33)] and 24 h [MD −2.33 mg morphine equivalents (95% CI: −4.39, −0.26)], required less rescue analgesia for intolerable pain [relative risk 0.80 (95% CI: 0.69, 0.93)], had longer time to first dose of analgesic [MD 12.06 min (95% CI: 0.80, 23.32)], and shorter stays in the post-anaesthesia care unit [MD −5.32 min (95% CI: −10.49 to −0.15)]. There was no dose–response with regard to the opioid-sparing effect. There was no increase in infection or delayed wound healing with dexamethasone, but blood glucose levels were higher at 24 h [MD 0.39 mmol litre−1 (95% CI: 0.04, 0.74)].
A single i.v. perioperative dose of dexamethasone had small but statistically significant analgesic benefits.
PMCID: PMC3544008  PMID: 23220857
analgesics, opioid; dexamethasone; glucocorticoids; hyperglycaemia; pain, postoperative; surgical wound infection
17.  Opioids Switching with Transdermal Systems in Chronic Cancer Pain 
Due to tolerance development and adverse side effects, chronic pain patients frequently need to be switched to alternative opioid therapy
To assess the efficacy and tolerability of an alternative transdermally applied (TDS) opioid in patients with chronic cancer pain receiving insufficient analgesia using their present treatment.
A total of 32 patients received alternative opioid therapy, 16 were switched from buprenorphine to fentanyl and 16 were switched from fentanyl to buprenorphine. The dosage used was 50% of that indicated in equipotency conversion tables. Pain relief was assessed at weekly intervals for the next 3 weeks
Pain relief as assessed by VAS, PPI, and PRI significantly improved (p < 0.0001) in all patients at all 3 follow up visits. After 3 weeks of treatment, the reduction in the mean VAS, PPI, and PRI scores in the fentanyl and buprenorphine groups was 68, 77, 74, and 69, 79, and 62%, respectively. Over the same time period the use of oral morphine as rescue medication was reduced from 27.5 ± 20.5 (mean ± SD) to 3.75 ± 8.06, and 33.8 ± 18.9 to 3.75 ± 10.9 mg/day in the fentanyl and buprenorphine groups, respectively. There was no significant difference in either pain relief or rescue medication use between the two patient groups The number of patient with adverse events fell during the study. After the third week of the treatment the number of patients with constipation was reduced from 11 to 5, and 10 to 4 patients in the fentanyl and buprenorphine groups, respectively. There was a similar reduction in the incidence of nausea and vomiting. No sedation was seen in any patient after one week of treatment.
Opioid switching at 50% of the calculated equianalgesic dose produced a significant reduction in pain levels and rescue medication. The incidence of side effects decreased and no new side effects were noted. Further studies are required to provide individualized treatment for patients according to their different types of cancer.
PMCID: PMC2684533  PMID: 19422676
18.  The impact of epidural analgesia compared to systemic opioid-based analgesia with regard to length of hospital stay and recovery of bowel function: retrospective evaluation of 1555 patients undergoing thoracotomy 
To assess the protocols of epidural analgesia versus systemic opioid-based analgesia retrospectively in 1555 thoracotomies in our thoracic centre during 2011–2013.
Pain therapy is aggressive and standardized in our thoracic centre thoughout the complete postoperative stay. Patients receive either standardized epidural analgesia with ropivacaine + sufentanil 4–8 mls/h (500 mls bag) and are bridged when the epidural bag is finished to a standardized controlled-release oxycodone protocol with non opioid every 6 hours (EDA Group), or patients receive immediately postoperative standardized oral analgesic protocol with controlled-released oxycodone and non opioid every 6 h (Opioid Group). All patients are visited daily by a pain specialist throughout the whole stay.
Data of 1555 thoracotomies from 2011–2013 were analysed, 838 patients in the EDA Group and 717 patients in the Opioid Group. There was no difference with regard to sex or age between groups. 7.5% of patients in the EDA Group and 13% in the Oxy Group had a preexisting pain therapy (p = 0.001). In the EDA Group epidural analgesia was performed for 4.6 ± 1.5 days. Length of hospital stay was the same in both groups (EDA: 9.9.6 ± 4.9 vs Opioid: 9.6 ± 5.8 days). 84.7% of patients in the EDA Group and 79.1% of patients of the Oxy Group were dismissed with oral opioid (p < 0.004). When patients were dismissed with opioid medication patients in the EDA Group were dismissed with higher oxycodone opioid doses than patients in the Opioid Group (29.5 ± 15.2 mg vs 26.9 ± 15.2 mg, p = 0.01). There was no difference with regard to dejection time between the two groups (EDA: 3.8 ± 2.2 days vs Opioid: 3.7 ± 1.6 days, n.s.).
We first present data monitoring postoperative analgesic protocols after thoracotomies throughout the whole stay in hospital until dismission. Our retrospective data indicate that patients with epidural analgesia stay as long in hospital as patients with systemic opioid based therapy. Patients with initial epidural analgesia are dismissed with higher oxycodone opioid doses than patients with initial opioid based postoperative analgesia. We found no difference in recovery of bowel function.
Study limitations
The study design is retrospectively and results might be biased.
PMCID: PMC4246432  PMID: 25417134
Major thoracic surgery; Postoperative analgesia; Epidural analgesia; Oxycodone; Hospital stay; Bowel function
19.  The Effect of Nitrous Oxide Anesthesia on Early Postoperative Opioid Consumption and Pain 
Background and Objectives
Many patients experience moderate to severe postoperative pain. Nitrous oxide exerts analgesia by inhibition of N-Methyl-D-aspartate (NMDA) receptors. Ketamine, another NMDA receptor-antagonist, reduces postoperative opioid consumption and pain. A similar effect of nitrous oxide is plausible, yet understudied. The goal of this study was to determine the effects of nitrous oxide anesthesia on early postsurgical opioid consumption and pain.
This was a retrospective, secondary analysis of the Vitamins In Nitrous Oxide trial, where 500 patients undergoing general anesthesia for noncardiac surgery received 60% nitrous oxide and 125 received no nitrous oxide (otherwise, inclusion/exclusion criteria were identical). Exclusion criteria for this study were regional anesthesia; not extubated after surgery; transfer to ICU; no available PACU record; postsurgical sedation; or treated with naloxone. Primary outcomes were cumulative opioid consumption measured in morphine equivalents and pain scores during the immediate recovery phase.
Four hundred forty-two patients met inclusion criteria. No difference in intraoperative and postoperative opioid consumption was observed between patients who received nitrous oxide (n=353) and patients who did not (n=89). The median [interquartile range] postoperative morphine equivalent dose was 6.7 mg [1.7–14.1] for patients who received nitrous oxide and 6.7 mg [2.1–15.4] for patients who did not (P = 0.73). The maximum pain score was 6 [4–8] for patients who received nitrous oxide versus 6 [3–8] for patients who received nitrous oxide-free anesthesia (P = 0.52). The prevalence of moderate to severe pain was 69% for patients who received nitrous oxide and 68% for patients who did not (P = 0.90).
Nitrous oxide anesthesia was not associated with decreased opioid administration, pain, or incidence of moderate to severe pain in the early postoperative phase.
PMCID: PMC3919543  PMID: 24310050
Analgesia; Nitrous Oxide; Pain; Postoperative; Anesthesia; General
20.  Care management practices for chronic pain in veterans prescribed high doses of opioid medications 
Family Practice  2013;30(6):671-678.
There is growing interest in the primary care management of patients with chronic non-cancer pain (CNCP) who are prescribed long-term opioid therapy.
The aim of this study was to examine the care management practices and medical utilization of patients prescribed high doses of opioids relative to patients prescribed traditional doses of opioids.
We conducted a retrospective cohort study of veterans who had CNCP in 2008 and reviewed medical care for the prior 2 years. Patients with CNCP who were prescribed high-dose opioid therapy (≥180mg morphine equivalent per day for 90+ consecutive days; n = 60) were compared with patients prescribed traditional dose opioid therapy (5–179mg morphine equivalent per day for 90+ consecutive days; n = 60).
Patients in the high-dose group had several aspects of documented care that differed from patients in the traditional dose group, including more medical visits, attempting an opioid taper, receiving a urine drug screen and developing a pain goal. The majority of variables that were assessed did not differ between groups, including documented assessments of functional status or co-morbid psychopathology, opioid rotation, discussion of treatment side effects, non-pharmacological treatments or collaboration with mental health or pain specialists.
Further work is needed to identify mechanisms for optimizing care management for patients with CNCP who are prescribed high doses of opioid medications.
PMCID: PMC3896000  PMID: 23901065
Chronic pain; clinical treatment guidelines; high-dose opioids; opioids; primary care.
21.  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.
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.
PMCID: PMC3546208  PMID: 23342205
cancer pain; complications; efficacy; intrathecal morphine; side effects
22.  Opioid Infusions in the Neonatal Intensive Care Unit 
The primary objective of this study was to compare the use of opioid infusions to that proposed in guidelines published in an in-house medication handbook. Secondary objectives were to assess the documented use of a standardized neonatal pain assessment tool and to describe the supplemental use of opioids concurrent with an opioid infusion.
A retrospective chart review was performed for all patients in the NICU who received opioid infusions between November 1, 2005, and November 30, 2006. Data collected included patient characteristics, opioid infusion dosing and duration, supplemental opioid use, and pain assessment documentation.
Of the110 neonates who received morphine or fentanyl during the study period, 65 patients met inclusion criteria. Reasons for starting an opioid infusion included nonsurgical sedation and/or analgesia (51%), postoperative pain (17%), and procedural pain (1%). No reason was documented for 31% of patients. Thirtyeight percent of neonates received a loading dose of opioid before initiation of the infusion. The median dose was 100 mcg/kg (IQR=48.2) for morphine and and 1 mcg/kg (IQR=0.8) for fentanyl. The mean ± SD starting rates of morphine and fentanyl infusions were 12.3 ± 4.7 mcg/kg/hr and 1.5 ± 1.7 mcg/kg/hr, respectively. Supplemental opioid doses were given to 46% of neonates during the infusion period. Supplemental doses were given for procedures (69%) and pain/agitation/sedation (26%). No reason was documented for 5% of patients. The Neonatal Pain, Agitation and Sedation Scale scores were only documented 9% of the time for each day that the patient received an opioid infusion.
Dosing of opioids generally was within the recommendations that are described in the in-house medication handbook. A substantial percentage of neonates received supplemental opioid doses while on opioid infusions, mostly for procedural pain management. Documentation of the reason for using opioid infusions and the assessment of neonatal pain was poor.
PMCID: PMC3018177  PMID: 22477805
analgesics; infants; intensive care units; newborn; neonate; opioid
23.  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.
PMCID: PMC2795073  PMID: 19692203
Pain; genes; cytokines; epidemiology; cancer; analgesia; molecular epidemiology
24.  Feasibility Study of Rapid Opioid Rotation and Titration 
Pain physician  2011;14(1):71-82.
Opioid guidelines recommend opioid rotation and switching for patients who do not achieve adequate pain relief or who experience intolerable adverse events (AEs) with their current opioid. However, specific recommendations and protocols for opioid rotation are lacking, making the practice time consuming and difficult for primary care physicians to accomplish independently or coordinate with a pain specialist.
To assess the safety and feasibility of using 24-hour intravenous patient-controlled analgesia (IV-PCA) to achieve rapid opioid rotation and titration (RORT).
Study design
Open-label pilot study.
Hospital research center.
At admission, patients (aged ≥ 18 years) with treatment-refractory chronic pain who were taking morphine or oxycodone for ≥ 3 months and had pain scores ≥ 4 on a 10-point scale, underwent opioid rotation to oral oxymorphone extended release (ER). They also received IV-PCA oxymorphone for 24 hours as needed. At discharge, the participants were taking oral oxymorphone ER with oxymorphone immediate release (IR) as needed based on their total 24-hour oral plus IV-PCA oxymorphone use. During a 2-week follow-up, their oxymorphone usage was titrated as needed. Main outcome measures were AEs, Patient Global Impression of Change (PGIC), Brief Pain Inventory (0 = no pain/interference, 10 = worst pain/complete interference), treatment satisfaction, and change in oxymorphone dose.
Twelve patients enrolled and completed the 24-hour IV-PCA; 10 completed the 2-week follow-up post-24-hour IV-PCA. PGIC status improved by 12 hours (odds ratio [OR], 0.19, 95% CI, 0.08–0.44; P < 0.001), and both PGIC status and activity scores improved by 24 hours (OR, 0.23, 95% CI, 0.09–0.55; P = 0.001; OR, 0.49, 95% CI, 0.25–0.96; P = 0.04, respectively) and 2 weeks (OR, 0.14, 95% CI, 0.04–0.46; P = 0.001; OR, 0.21, 95% CI, 0.06–0.72; P = 0.01) versus 6 hours. During the 24-hour IV-PCA time period, 6 of 10 patients accomplished ≥ 50% of their overall dose titration. At 2 weeks, 8 of 10 participants were Greatly Satisfied or Somewhat Satisfied with the overall RORT procedure. RORT was well tolerated, with no serious AEs.
This was a pilot open-label study in a small number of participants. A larger randomized study with long-term follow-up and comparison to traditional protocols is necessary.
Preliminary data suggest that RORT can be performed safely and effectively by incorporating IV-PCA during the first 24 hours. Further investigations are needed to determine whether RORT can become an ambulatory treatment intervention in pain practice.
PMCID: PMC3197741  PMID: 21267044
chronic pain; opioid rotation; opioid switching; opioid substitution; opioid conversion; oxymorphone; oxycodone; morphine
25.  Emergency Department Visits Among Recipients of Chronic Opioid Therapy 
Archives of internal medicine  2010;170(16):1425-1432.
There has been an increase in over dose deaths and emergency department visits (EDVs) involving use of prescription opioids, but the association between opioid prescribing and adverse outcomes is unclear.
Data were obtained from administrative claim records from Arkansas Medicaid and HealthCore commercially insured enrollees, 18 years and older, who used prescription opioids for at least 90 continuous days within a 6-month period between 2000 and 2005 and had no cancer diagnoses. Regression analysis was used to examine risk factors for EDVs and alcohol- or drug-related encounters (ADEs) in the 12 months following 90 days or more of prescribed opioids.
Headache, back pain, and preexisting substance use disorders were significantly associated with EDVs and ADEs. Mental health disorders were associated with EDVs in HealthCore enrollees and with ADEs in both samples. Opioid dose per day was not consistently associated with EDVs but doubled the risk of ADEs at morphine-equivalent doses over 120 mg/d. Use of short-acting Drug Enforcement Agency Schedule II opioids was associated with EDVs compared with use of non–Schedule II opioids alone (relative risk range, 1.09–1.74). Use of Schedule II long-acting opioids was strongly associated with ADEs (relative risk range, 1.64–4.00).
Use of Schedule II opioids, headache, back pain, and substance use disorders are associated with EDVs and ADEs among adults prescribed opioids for 90 days or more. It may be possible to increase the safety of chronic opioid therapy by minimizing the prescription of Schedule II opioids in these higher-risk recipients.
PMCID: PMC3715046  PMID: 20837827

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