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Journal of Opioid Management
January/February 2006, Volume 2
, Number 1


Article
News briefs
January/February 2006; pages 13-15

Abstract
NIH Announces New Request for Grant Applications. Update on 2006 AAOP Scientific Meeting location. New protocol for medication-assisted treatment of opioid addiction. Drug dispensing law in New York State. Push for online drug regulations in West Virginia. Lawsuit in death of patient using fentanyl patch. SAMHSA grant renewed. SeroquEl and opiate withdrawal.


Article
Literature review. Iatrogenic addiction in patients treated for acute or subacute pain: A systematic review
Ajay D. Wasan, MD, MSc; Darin J. Correll, MD; Igor Kissin, MD, PhD; Sarah O’Shea, BA; Robert N. Jamison, PhD
January/February 2006; pages 16-22

Abstract
We conducted a systematic review of the literature on the evidence for iatrogenic addiction in patients treated for acute and subacute pain. Literature searches yielded 1,943 articles, 53 of which were reviewed in detail, and 41 of which met criteria for inclusion in the review of iatrogenic addiction. Two authors independently reviewed and summarized the findings of each article. Discrepancies of ratings were resolved by discussion. We identified no randomized trials or comparative longitudinal studies. The results of nine studies of low methodological quality suggest conflicting findings. This manuscript discusses some possible mechanisms of iatrogenic addiction and concludes with suggestions for methodologically stronger studies to provide more definitive data regarding the evidence for or against iatrogenic addiction in patients treated for acute and subacute pain. The systematic review of the literature could not adequately answer the study questions; thus, it is not known whether the risk for iatrogenic addiction among patients treated with opioids for acute or subacute pain is relatively high (> 10 percent) or low (< 0.1 percent). Key words: iatrogenic addiction, acute pain, opioids, substance abuse


Article
Literature review. Problematic terminology for problematic drug use
David Cowan, MD, BSc (Hons), PhD
January/February 2006; pages 23-30


Article
Opioids in the parturient with chronic nonmalignant pain: A retrospective review
Ibrahim Hadi, MD, FRCPC; Orlando da Silva, MD, FRCPC; Renato Natale, MD, FRCSC; David Boyd, MD, FRCPC; Patricia K. Morley-Forster, MD, FRCPC
January/February 2006; pages 31-34

Abstract
The purpose of this research was to determine the neonatal outcomes of women who had been taking medically prescribed opioids throughout their pregnancy. A retrospective case study was done of 15 pregnancies associated with maternal opiate use between January 1, 1999, and September 30, 2002. Two cases were excluded due to coaddiction. Neonatal data were collected including gestational age, head circumference, length, birth weight, Apgar score at one and five minutes, details of resuscitation required, and Neonatal Abstinence Score. There were 13 pregnancies, which resulted in 13 live births; opioids prescribed included oxycodone, codeine, meperidine, fentanyl, dilaudid, morphine, and methadone. There were four babies with one-minute Apgar score = 5, and two babies with five-minute Apgar score = 5. It was concluded that neonatal growth markers in this population were within normal limits as plotted on the standard growth and development record of Gairdner-Pearson. Five out of 13 (38.5 percent) neonates were diagnosed with opioid discontinuation syndrome. Key words: opioids, prescription, pain, pregnancy, neonatal development


Article
Barriers and facilitators to methadone maintenance therapy use among illicit opiate injection drug users in Vancouver
Cody Callon, BSc; Evan Wood, PhD; David Marsh, MD; Kathy Li, PhD; Julio Montaner, MD; Thomas Kerr, PhD
January/February 2006; pages 35-41

Abstract
Methadone maintenance therapy (MMT) has been increasingly implemented as the treatment of choice for opiate-addicted individuals and has been associated with reduced harm related to opiate addiction. Barriers to MMT uptake still exist, however, and many opiate-addicted individuals do not access this form of treatment. We examined barriers to and facilitators of MMT access among opiate users enrolled in a prospective cohort study of injection drug users (IDUs). We identified individuals who had initiated MMT during follow-up interviews and used generalized estimating equations to identify sociodemographic and drug-related variables associated with MMT access. Of the 1,587 participants recruited into the Vancouver Injection Drug User Study, 1,463 individuals were eligible for the present analysis. Factors negatively associated with MMT use included male gender (odds ratio [OR] = 0.41; 95 percent confidence interval [CI], 0.32 to 0.52), Aboriginal ethnicity (OR = 0.37; 95 percent CI, 0.29 to 0.48), recent incarceration (OR = 0.82; 95 percent CI, 0.72 to 0.93), Downtown Eastside residence (OR = 0.86; 95 percent CI, 0.75 to 0.97), sex-trade involvement (OR = 0.80; 95 percent CI, 0.67 to 0.95), syringe lending (OR = 0.76; 95 percent CI, 0.66 to 0.89), denied addiction treatment (OR = 0.81; 95 percent CI, 0.68 to 0.96), heroin injection (OR = 0.51; 95 percent CI, 0.44 to 0.59), nonfatal overdose (OR = 0.59; 95 percent CI, 0.51 to 0.68), and injecting in public (OR = 0.75; 95 percent CI, 0.63 to 0.89). Older age (OR = 1.03; 95 percent CI, 1.01 to 1.04), human immunodeficiency virus (HIV) positivity (OR = 1.89; 95 percent CI, 1.52 to 2.23), and crack cocaine smoking (OR = 1.41; 95 percent CI, 1.22 to 1.62) were positively associated with MMT use. Our study identified a large number of barriers to and facilitators of MMT use among IDUs. While some populations such as HIV-positive individuals are frequently accessing MMT, identified barriers among men and Aboriginal IDUs are of great concern. These findings indicate the need for additional interventions aimed at maximizing coverage of MMT and other treatments for opiate-addicted individuals. Key words: methadone maintenance therapy, injection drug use, opiate addiction, treatment


Article
Case study. Poor pain relief and possible toxicity from high-dose intrathecal opioid treatment: Report of two cases
Anca Popescu, MD; Rajorshi Mitra, MD; Jane Ballantyne, MD, FRCA
January/February 2006; pages 43-47


Article
Case study. High-dose methadone and QTc prolongation: Strategies to optimize safety
John Schmittner, MD
January/February 2006; pages 49-55

Journal of Opioid Management
March/April 2006, Volume 2
, Number 2


Article
Review of issue. The law and pain
Christopher V. Rowland, Jr., MD
March/April 2006; pages 66-66


Article
News briefs
March/April 2006; pages 71-72

Abstract
Affirmation of States’ Authority. Knowing how to play the game; abusers’ pain relief. Acute pain and narcotic use does not impair the ability to provide informed consent. Massive Amounts of Pain Medication.


Article
Editorial. The US Supreme Court decision on assisted suicide and the prescription of pain medication: Limit the celebration
Marshall B. Kapp, JD, MPH
March/April 2006; pages 73-74


Article
Legal perspective. A summary of current Drug Enforcement Administration positions and resulting federal legal and regulatory “standards”
Jennifer Bolen, JD
March/April 2006; pages 75-80


Article
Case report. A descriptive case series: Oral transmucosal fentanyl use in patients with noncancerous pain
Anthony H. Guarino, MD; Jennifer Myers, RN, MSN, ANP; Martha E. Cornell, RN, BSN
March/April 2006; pages 81-87

Abstract
Transmucosal fentanyl is indicated for patients with cancer who are opioid tolerant, but it is also used for the treatment of noncancerous pain. The following is a survey study of the use of transmucosal fentanyl in 29 patients with noncancerous pain in an academic, community-based pain management practice. Transmucosal fentanyl was found to be safe and efficacious in the patients studied. Key words: transmucosal fentanyl, Actiq, noncancerous pain, breakthrough pain, opioid


Article
Pharmacy perspective. Early administration of oral morphine to orthopedic patients after surgery
Ruth Zaslansky, DSc; Elon Eisenberg, MD; Bezalel Peskin, MD; Elliot Sprecher, PhD; Daniel N. Reis, MD; Chaim Zinman, MD; Silviu Brill, MD
March/April 2006; pages 88-92

Abstract
Current pain treatment guidelines advise against providing analgesics for postoperative pain using intramuscular injections, as this generally provides poor pain relief. However, this route remains the most prevalent treatment method. Intravenous or epidural patient-controlled-analgesia methods reduce pain effectively but are expensive, labor intensive, and available to only a limited number of patients. We propose administering the analgesics using oral analgesics and have developed a simple protocol for treating postoperative pain by use of oral morphine. After a variety of orthopedic surgeries, patients were given “around-the-clock,” oral, immediate-release morphine. Efficacy of the treatment (pain scores and adverse effects) was assessed 24 ± 2 hours after surgery. Data were collected prospectively from 95 patients, who received an average of 61 ± 30 (SD) mg morphine. Average pain scores were 2.4/10 (± 1.4) at rest and 4.0/10 (± 1.4) during movement in bed. Nausea and vomiting, the most common adverse effects, were reported by 22 (23 percent) patients. Naloxone was not administered to any of the patients. Oral morphine given in the early postoperative time to patients after a variety of orthopedic surgeries was effective and safe. Key words: postoperative pain, oral analgesics, oral morphine, orthopedic surgery


Article
Opioids and Down’s syndrome
Federica Mafrica, MD; Vincenzo Fodale, MD
March/April 2006; pages 93-98

Abstract
Opioids are used in clinical practice for sedation, anesthesia, and analgesia. Their effects depend on their pharmacokinetic and pharmacodynamic characteristics. The liver is the major site for the biotransformation of most opioids. The major metabolic pathway is oxidation. Metabolism influences distribution, clearance, onset, and offset of opioid drugs. Action also depends on the coupling of opioids with the class of receptors involved and on localization of specific receptors. Three major types of opioid receptors, designated as m, d, and k, present in the central nervous system, are coupled to G proteins and inhibit adenylyl cyclase. Down’s syndrome is a congenital condition characterized by mental retardation and particular physical features. Neurotransmission alterations are important. Alteration in the concentration of opioids in the cortex of these patients has been demonstrated. Neurobiological abnormalities and, in some, abnormalities in the neurotransmission systems, anxiety, and, in particular, nociception all suggest that structural and functional alterations of opioid receptors may be present. A clear knowledge of these multiple abnormalities is essential for skillful management of the perioperative period and for a good outcome for patients with Down’s syndrome. Key words: opioids, Down’s syndrome, neurotransmission alterations, neurobiological abnormalities


Article
A comparison of patient-controlled epidural pethidine vs. nurse-administered epidural pethidine for analgesia after caesarean section
Yvonne Lim, Mmed; Sally Wilson; Steven Katz, MD
March/April 2006; pages 99-104

Abstract
Patient-controlled epidural analgesia with pethidine for post-caesarean section patients has been shown to be efficacious. However, no studies to date have compared it with intermittent nurse-administered epidural pethidine. The aim of this study was to compare the analgesia efficacy, pethidine requirement, side effects, and nurses’ and patients’ satisfaction with these two techniques in post-caesarean section patients. After obtaining informed patient consent, we recruited 34 patients undergoing elective lower-segment caesarean section. A combined spinal epidural technique was used to provide anesthesia for all patients, and 50 mg pethidine was given epidurally at the end of the operation. Patients were assigned to two groups: group P (n = 17) received patient-controlled epidural analgesia with pethidine (25 mg of five mg/ml solution, lockout of 10 minutes and maximum dose of 150 mg/four hours), and group N (n = 17) received nurse-administered epidural pethidine (bolus of 50 mg and maximum dose of 50 mg/two hours) when required. We collected data at six, 12, 24, 36, and 48 hours following initiation of anesthesia. Visual analogue pain scores (median) were lower in group P than in group N, both on movement and at rest, at six, 12, 24, 36, and 48 hours postoperatively (p < 0.05). Total pethidine consumption (median) and frequency of side effects were similar in both groups. Patients in group P exhibited a trend toward earlier return to activities of daily living and care for the newborn; however, this did not reach statistical significance, and there was no difference in maternal satisfaction between the two groups. Satisfaction scores of nurses caring for patients in group P were higher than for those in group N (median 100 mm, interquartile range [IQR] 90 to 100, vs. median 90 mm, IQR 80 to 90, p < 0.05). Patient-controlled epidural analgesia with pethidine improved patients’ pain scores after caesarean section when compared with intermittent nurse-administered epidural pethidine. Regarding the mode of delivery of postoperative analgesia, we noted a higher satisfaction score among nurses caring for group P than among those caring for group N. Key words: post-caesarean section analgesia, epidural analgesia, patient-controlled analgesia, pethidine


Article
Effect of drug and medical treatment on wide geographic variations in repeated emergency department use by HIV-infected drug users
Barbara J. Turner, MD, MSEd; Christine Laine, MD, MPH; Alan Kott; Walter W. Hauck, PhD
March/April 2006; pages 105-112

Abstract
Repeated (³ two visits) emergency department (ED) visits by HIV-infected (HIV+) drug users in New York State (NYS) vary widely by region and may reflect regional inequities in receipt of needed drug treatment and medical services. The study’s objective was to evaluate receipt of drug treatment and medical care by HIV+ drug users by region and its effect on ED use. For NYS Medicaid-enrolled HIV+ drug users (N = 11,556) in 1996 and 1997, we identified receipt of long-term (³ six months) drug treatment, HIV care, and a usual source of medical care from claims files. Regions were classified as New York City , downstate suburban, upstate urban, and rural/small city. We examined adjusted associations of these services with ³ two ED visits in the entire cohort and separately among patients who do and do not receive these three types of services. Repeated ED visits were greatest in rural/small cities (40.7 percent) and least in New York City (24.1 percent; p < 0.001), and receipt of drug treatment was also poorest (p < 0.001) in rural/small cities, whereas receipt of HIV care and usual source of medical care varied less by region. Adjusted odds of ³ two ED visits was increased for patients in rural/small cities (1.89 [confidence interval, 1.44 to 2.50]) vs. New York City and reduced for patents with long-term drug treatment (0.76 [confidence interval, 0.69 to 0.84]). Among persons receiving long-term drug treatment, observed regional differences in ED use largely disappeared. Regional variations in receipt of long-term drug treatment by HIV+ drug users in one state appear to contribute to large differences in ED utilization. Key words: HIV-infected drug users, emergency department visits, long-term drug treatment, regional inequities

Journal of Opioid Management
May/June 2006, Volume 2
, Number 3


Article
Conference review. Inaugural Opioid Certification Program
Christopher V. Rowland, Jr., MD
May/June 2006; pages 120-121


Article
Commentary. Reality and responsibility: A commentary on the treatment of pain and suffering in a drug-using society
Steven D. Passik, PhD; Howard Heit, MD, FACP, FASAM; Kenneth L. Kirsh, PhD
May/June 2006; pages 123-127

Abstract
While opioids are a necessary part of the armamentarium of pain management, there has been a growing trend toward prescription drug abuse and diversion in our society. Meeting the goal of treating pain while not contributing to drug abuse and diversion requires vigilance and education. Physicians and patients have been singled out as the main players in the societal problem of diversion of prescription drugs. In fact, the problem can only be overcome when not only physicians and patients but also healthcare practitioners, third-party payers, law enforcement agencies and regulators, the pharmaceutical industry, and the media finally work together to prevent it, instead of fingering any one party for the blame. Key words: opioids, pain management, prescription drug abuse, prescription drug diversion


Article
Legal perspective. Pain control for dying patients: Hastening death or ensuring comfort?
Marshall B. Kapp, JD, MPH
May/June 2006; pages 128-129


Article
Pharmaceutical update. Modafinil: Is it ready for prime time?
Eric Prommer, MD
May/June 2006; pages 130-136

Abstract
Psychostimulants have been used to treat many symptoms associated with advanced cancer. The primary role of psychostimulants in such cases is the treatment of symptoms such as cancer-related fatigue, opioid-induced sedation, depression, and cognitive dysfunction associated with malignancies. These uses for psychostimulants came after approval for treatment of disorders such as attention deficit disorder. Modafinil, a new psychostimulant, is following a similar path after its approval for use in attention deficit disorder in 1998. Modafinil has been used to treat fatigue associated with neurodegenerative disorders such as multiple sclerosis and amyotrophic lateral sclerosis. It is now being increasingly used for cancer-related symptoms targeted by psychostimulants. Preliminary evidence from literature review suggests that modafinil is efficacious in improving opioid-induced sedation, cancer-related fatigue, and depression. There is no evidence to support its use in the treatment of cognitive dysfunction related to cancer or to support its having analgesic properties. Well-designed, randomized, controlled clinical trials are still needed to further elucidate the precise role of this drug in the care of patients with cancer. Specifically, large placebo-controlled trials with modafinil must be conducted in patients with cancer, with specific attention paid to pain control, depression, cognitive function, and adverse effects. Key words: modafinil, reticular activating system, psychostimulants


Article
Adverse effects and cognitive function among primary care patients taking opioids for chronic nonmalignant pain
Randall T. Brown, MD; Megan Zuelsdorff, BS; Michael Fleming, MD, MPH
May/June 2006; pages 137-146

Abstract
Chronic opioid therapy is commonly prescribed for chronic nonmalignant pain. Few published data describe the adverse effects experienced by patients with chronic nonmalignant pain being treated by primary care physicians. A prevalence study was conducted on a sample of 1,009 patients (889 receiving chronic opioids) being treated by 235 primary care physicians. Standardized questionnaires and medical record reviews were used to assess rates of addiction, pain diagnosis and severity, opioid adverse effects, and mental health. The mean daily dose of opioids was 92 mg using a morphine-equivalent conversion. Side effects included constipation (40 percent), sleeping problems (25 percent), loss of appetite (23 percent), and sexual dysfunction (18 percent), with patients on daily opioids experiencing more side effects than subjects on intermittent medication. The Medical Outcomes Study Mental Health Inventory (MOS-MHI) cognitive functioning scale indicated poorer cognitive function in the overall sample of chronic pain patients as compared to a general clinical sample (D x 95 percent CI = 9.28, 13.76). However, there were limited differences in MOS scores between chronic pain subjects on daily opioids vs. intermittent opioids vs. no prescription opioids. A regression model suggests that psychological measures and pain severity are more predictive of decrements in cognitive function than specific opioid preparations or daily opioid dose. Physicians should closely monitor patients for adverse effects and adequacy of pain control when using chronic opioid therapy for chronic pain treatment. Psychological health, an important predictor of cognitive dysfunction, is a particularly important measure to actively monitor and manage. Key words: opioids, adverse effects, chronic nonmalignant pain, primary care physicians


Article
Opioids and brain imaging
Shyam Balasubramanian, MBBS, MD, FRCA; Patricia Morley-Forster, MD, FRCPC; Yves Bureau, PhD
May/June 2006; pages 147-153

Abstract
Since the introduction of the gate-control theory, a plethora of evidence to support the spinal processing of pain signals has come to light. Cognitive and affective aspects of the pain experience indicate the importance of supraspinal structures, but the biological mechanisms have remained inadequately explored. Within the past decade, imaging techniques have emerged that enable in vivo assessment of the central opioidergic system and the central processing of pain. The two most important imaging modalities to this end are functional magnetic resonance imaging (fMRI) and positron emission tomography (PET). This article will describe the underlying principles of these techniques and explain their importance in determining the loci of opioidergic pathways and their neuromodulatory influence on acute and chronic pain conditions, role in placebo effects, implication in drug dependence, and potential role in studying the analgesic efficacy of new drugs. Key words: brain imaging, fMRI, PET, central opioid pathways, central pain processing


Article
The ACTION study: A randomized, open-label, multicenter trial comparing SID ER morphine sulfate capsules (AVINZA®) to BID controlled-release oxycodone hydrochloride tablets (OxyContin®) for the RX of chronic, moderate to severe low back pain
Richard L. Rauck, MD; Stephen A. Bookbinder, MD; Timothy R. Bunker, MD; Christopher D. Alftine, MD; Richard Ghalie, MD; Andres Negro-Vilar, MD, PhD; Egbert de Jong, MD; Steven Gershon, MD
May/June 2006; pages 155-166

Abstract
This large, open-label, randomized, parallel-group, multicenter study compared two oral sustained-release opioids (SROs)—AVINZA® (A-MQD), morphine sulfate extended-release capsules given once a day, and OxyContin® (O-ER), oxycodone modified-release tablets given twice a day—in SRO-naive subjects ages 30 to 70 with chronic, moderate to severe low back pain. Of the 392 subjects enrolled and randomized, 266 (132 in the A-MQD group and 134 in the O-ER group) completed the opioid dose titration phase and entered an eight-week evaluation phase. During the evaluation phase, A-MQD achieved significantly better pain control than O-ER, as demonstrated by a greater decrease from baseline in pain scores obtained four times daily during weeks one, four, and eight (p = 0.002). The number of breakthrough-pain rescue medication doses adjusted for the number of patient days was significantly lower in the A-MQD group (p < 0.0001). Better pain control with A-MQD was achieved with a significantly lower daily opioid dose than with O-ER (mean 69.9 mg and 91 mg morphine equivalents, respectively; p = 0.0125). Quality of sleep was significantly better with A-MQD for the entire evaluation phase (p = 0.0026). The incidence and severity of elicited opioid side effects were similar in the two groups. This trial demonstrated that once-daily A-MQD provides consistent around-the-clock pain relief in patients with low back pain. In patients who completed opioid dose titration, A-MQD was significantly better than O-ER for reducing pain and improving sleep, while requiring a lower daily opioid dose. Key words: AVINZA, OxyContin, chronic low back pain


Article
A Phase II, multicenter, randomized, double-blind, placebo-controlled crossover study of CJC-1008—a long-acting, parenteral opioid analgesic—in the treatment of postherpetic neuralgia
Mark S. Wallace, MD; Dwight Moulin, MD; A. J. M. Clark, FRCPC; Ronald Wasserman, MD; Ann Neale; Patricia Morley-Forster, MD; Jean-Paul Castaigne, MD; Sam Teichman, MD
May/June 2006; pages 167-173

Abstract
Introduction: CJC-1008 is a chemical modification of the opioid peptide dynorphin A (1-13) (Dyn A) that promotes dynorphin’s covalent attachment to human serum albumin in vivo after administration, thus prolonging its duration of action. The primary objective of this study was to evaluate the preliminary efficacy and safety of CJC-1008 as compared with placebo in patients with postherpetic neuralgia (PHN). Methods: Patients with PHN were assigned 1:1 to receive active study medication or placebo. After dosing, measurements were made every 15 minutes for the first hour; at two, three, four, six, and eight hours postdose; and during return visits to the study site after two, seven, and 28 days (as necessary), as well as during precrossover and exit visits. These measurements examined: 1) overall pain intensity, 2) pain intensity for each individual PHN type, 3) categorical overall pain intensity, 4) categorical pain relief, and 5) adverse events (AEs). When PHN pain intensity returned to baseline and/or at patients’ first request for rescue analgesia other than acetaminophen (typically around 28 days after dosing but sometimes as soon as two days postdose), patients were to cross over to the alternative treatment and be monitored on the same schedule. Results: A substantial placebo response was observed, but the analgesic effect observed in the active group was greater than that in the placebo group for the first eight hours. By 24 hours, the difference was not significant. A total of 29 out of 30 patients (96 percent) experienced at least one treatment-emergent AE during active drug treatment, while 14 of 27 patients (52 percent) reported such AEs during placebo treatment. Of the AEs occurring within the first eight hours after dosing, 97 percent were reported during treatment with active drug and 3 percent were reported during treatment with placebo. The majority of these AEs were mild in intensity. Discussion: This study provides evidence of a greater analgesic effect when using CJC-1008 compared to placebo in patients with PHN. However, the effect only lasted through eight hours postdose and diminished by 24 hours. This study provides evidence of a peripheral action of dynorphin, since CJC-1008 does not cross the blood-brain barrier. Key words: CJC-1008, dynorphin, postherpetic neuralgia, placebo response


Article
Case report. Morphine toxicity in renal failure
Ferraz Gonçalves, MD
May/June 2006; pages 174-176

Journal of Opioid Management
July/August 2006, Volume 2
, Number 4


Article
Editorial. Opioid safety
Robert E. Enck, MD
July/August 2006; pages 183-183


Article
Calendar
July/August 2006; pages 184-184


Article
Legal perspective. Getting Informed Consent and Agreement for Treatment right: A legal perspective on key obligations for practitioners who use controlled substances to treat chronic pain
Jennifer Bolen, JD
July/August 2006; pages 193-200


Article
Case report. Dexmedetomidine to treat opioid withdrawal in infants following prolonged sedation in the pediatric ICU
Joseph D. Tobias, MD
July/August 2006; pages 201-205

Abstract
This retrospective study aims to report on the use of dexmedetomidine to treat opioid withdrawal following sedation during mechanical ventilation in a cohort of infants. Seven infants in the pediatric intensive care unit of a tertiary care center, ranging in age from three to 24 months (12.4 ± 8.2 months) and in weight from 4.6 to 15.4 kgs (9.9 ± 4.2 kgs), had received a continuous fentanyl infusion, supplemented with intermittent doses of midazolam for sedation, during mechanical ventilation. Withdrawal was documented by a Finnegan score ³ 12. Dexmedetomidine was administered as a loading dose of 0.5 mg/kg/hr, followed by an infusion of 0.5 mg/kg/hr. Dexmedetomidine effectively controlled the signs and symptoms of withdrawal in the seven patients. Subsequent Finnegan scores were £ 7 at all times (median 4, range 1 to 7). Two patients required a repeat of the loading dose and an increase of the infusion to 0.7 mg/kg/hr. These two patients had received higher doses of fentanyl than the other five patients (8.5 ± 0.7 versus 4.6 ± 0.5 mg/kg/hr, p < 0.0005). No adverse hemodynamic or respiratory effects related to dexmedetomidine were noted. This report involves the largest cohort of patients to receive dexmedetomidine in the treatment of withdrawal following opioid and benzodiazepine sedation during mechanical ventilation. We conclude that dexmedetomidine offers a viable option for such issues in the pediatric intensive care unit (PICU) setting. Key words: dexmedetomidine, pediatric, opioid, opioid withdrawal


Article
Pharmacy perspective. Capnography monitoring during opioid PCA administration
Rob Hutchison, PharmD
July/August 2006; pages 207-208


Article
Single-dose extended-release epidural morphine for pain after hip arthroplasty
Gavin Martin, MD; Maximilian Hartmannsgruber, MD; Edward Riley, MD; Garen Manvelian, MD
July/August 2006; pages 209-218

Abstract
This randomized, double-blind study compared the safety and efficacy of a new single-dose extended-release epidural morphine (EREM) formulation for postoperative pain following hip arthroplasty. Patients were administered a single dose of EREM (10, 20, or 30 mg, n = 93) or a single epidural dose of placebo (n = 27) before surgery and general anesthesia. Following surgery, patients had access to fentanyl with the use of intravenous patient-controlled analgesia. Postoperative fentanyl use, time to first postoperative fentanyl use, pain intensity at rest and with activity, patient ratings of pain control, and adverse events were recorded. Compared with placebo-treated patients, single-dose EREM patients used less total supplemental fentanyl (p £ 0.049), had a longer time to first fentanyl use (p < 0.001), and were less likely to use any supplemental fentanyl (p £ 0.042). EREM-treated patients reported lower pain intensity for up to 48 hours postdose compared with placebo-treated patients. Single-dose EREM was effective for postoperative pain relief for up to 48 hours following hip arthroplasty, with a safety and tolerability profile consistent with that of other epidurally administered opioids. Key words: single-dose extended-release epidural morphine, postoperative pain management, orthopedic surgery


Article
Relative abuse potential of opioid formulations in Canada: A structured field study
Edward M. Sellers, MD, PhD, FRCPC; Reinhard Schuller, MSc; Myroslava K. Romach, MD; G. L. A. Horbay, PhD
July/August 2006; pages 219-227

Abstract
Introduction: While prescription opioids can improve quality of life through pain relief, they are susceptible to misuse. This field study characterizes the relative susceptibility and attractiveness of a new analgesic patch, with fentanyl embedded in a matrix material, compared to other opioid dose formulations. Methods: Recreational opioid abusers (N = 42; 31 male, 11 female) from three Canadian sites participated in structured interviews. They were presented with nine products, some of which were hypothetical (fentanyl [F], hydromorphone [H], and oxycodone [O] in each of three formulations: matrix patch [M], reservoir-type gel patch [G], and tablet [T]). The attractiveness and tampering potential of each product was ranked using two 7-point Likert scales (Value of Product and Likelihood to Tamper), an index representing the product of the two scales, a 17-item Opiate Attractiveness Scale (OAS), relative street value, and rank order of overall desirability. Nonparametric analyses were used to compare each product to the FM. Results: The FT, HT, and FM were highly valued and most likely to be tampered with. The products were ranked in decreasing order of desirability as follows: FT > HT > FM > FG > OT > HM > HG > OM > OG. On the OAS, FM was more attractive than all gel-patch products (p < 0.001), and OT was most attractive overall. FM was statistically similar to OT, FT, OM, and HT. Of the 42 subjects, 25 (60 percent) preferred the matrix patch to the gel patch. Of the 17 subjects who preferred the gel patch, 10 (59 percent) were from a region generally unfamiliar with that formulation. Conclusions: Fentanyl is attractive to opioid abusers regardless of formulation. In Canada, a fentanyl matrix patch may be at higher risk for diversion, tampering, and abuse than other transdermal opioid formulations. These findings should be confirmed by epidemiological studies. Comparative risk management programs should be part of the development of any new narcotic delivery system. Key words: opioid, abuse, risk, matrix patch, formulation, tampering


Article
The influence of chief complaint on opioid use in the emergency department
Kathleen Puntillo, RN, DNSc, FAAN; Martha Neighbor, MD; Garrett K. Chan, APRN, BC, PhD; Roxanne Garbez, RN, MS, ACNP
July/August 2006; pages 228-235

Abstract
The aim of this study was to explore factors influencing emergency department (ED) clinicians’ use of opioids in treating selected patients. Patients who either received or did not receive opioids in the ED, as well as their nurses and physicians, were interviewed before patient discharge. We found that the decrease in patients’ mean (SD) pain intensity from the time of admission to the ED (7.3 ± 2.4 on a 0 to 10 numeric rating scale) to discharge (5.0 ± 2.9) was statistically significant (t93 = 8.4, p < 0.001, 95 percent CI = 1.7, 2.8) for all groups except those with trauma-related pain. The factor that most frequently led physicians of patients with abdominal pain and nurses in general to administer no opioids was that the patient was “not in that much pain.” However, the patients in question had self-reported pain scores that indicated moderate pain. Our findings lead us to conclude that clinicians inaccurately infer severity of patient pain. This in turn can influence the prescription of opioids and the patient’s decrease in pain. Key words: pain, pain assessment, pain treatment, emergency department, decision making, opioids


Article
Literature review. Renal effects of opioid exposure: Considerations for therapeutic use
Kalpna Gupta, PhD; Marc L. Weber, MD
July/August 2006; pages 236-240

Abstract
In recent years, the discovery of peripheral opioid receptors has challenged the dogma of opioids interacting exclusively with the central nervous system. In this article, we describe the current understanding of the roles of opioids and opioid receptors in renal physiology and pathophysiology. The renal response to opioid exposure varies depending upon the specific opioid agonist, dose, and duration of exposure. The known acute effects of opioids on the kidney impact salt and water balance. The chronic effects of opioid exposure on kidney function are largely unknown, but collapsing glomerulopathy has been associated with chronic heroin abuse. Opioid exposure can lead to both physiological and architectural renal changes, and this may have important clinical implications. Since opioids are often used for pain management in patients with existing kidney disease, their role in kidney function warrants attention. Key words: opioid, morphine, kidney, renal function, endothelium

Journal of Opioid Management
September/October 2006, Volume 2
, Number 5


Article
Commentary. Malignant pain or malignant patients?
Michael Weaver, MD
September/October 2006; pages 259-261


Article
Legal perspective. The Fourth Circuit Court of Appeals’ decision in United States v. Hurwitz: An important victory for pain management professionals and those living with pain
Jennifer Bolen, JD
September/October 2006; pages 262-267


Article
Pharmacy perspective. Methadone for cancer-related neuropathic pain: A review of the literature
Rosemarie Mannino, MD; Patrick Coyne, MSN, APRN; Craig Swainey, MD; Lea Ann Hansen, PharmD; Laurie Lyckholm, MD
September/October 2006; pages 269-276

Abstract
Neuropathic pain is commonly seen in cancer patients, either as a direct result of the malignancy or as a consequence of the treatment rendered. In recent years, methadone has been utilized in the treatment of neuropathic pain because of its additional mechanism of action as an NMDA-receptor antagonist. In this paper we discuss the etiology of neuropathic pain in cancer patients, unique properties of methadone, and prior studies on methadone in this patient population. While methadone has been established as a cheap and effective agent in treating cancer pain, specific studies are needed comparing methadone to other opioids in the management of cancer-related neuropathic pain. Key words: neuropathic pain, NMDA receptors, methadone, morphine


Article
Significant pain reduction in chronic pain patients after detoxification from high-dose opioids
Michael J. Baron, MD, MPH; Paul W. McDonald, PhD
September/October 2006; pages 277-282

Abstract
Opioid tolerance is a well-established phenomenon that often occurs in patients taking opioids for the treatment of chronic pain. Typically, doctors need to periodically elevate patients’ opioid doses in an attempt to manage their underlying pain conditions, resulting in escalating opioid levels with only moderate to negligible improvement in pain relief. Recently, opioid-induced hyperalgesia has been recognized as a potential form of central sensitization in which a patient’s pain level increases in parallel with elevation of his or her opioid dose. Here, we report a retrospective study of patients undergoing detoxification from high-dose opioids prescribed to treat an underlying chronic pain condition which had not resolved in the year prior. All patients were converted to ibuprofen to manage pain, with a subgroup treated with buprenorphine during detoxification. Self-reports for pain scores were taken at first evaluation, follow-up visits, and termination. Twenty-one of 23 patients reported a significant decrease in pain after detoxification, suggesting that high-dose opioids may contribute to pain sensitization via opioid-induced hyperalgesia, decreasing patient pain threshold and potentially masking resolution of the preexisting pain condition. Key words: opioid, tolerance, hyperalgesia, sensitization, detoxification, buprenorphine


Article
Prescription opioid abuse among drug-involved street-based sex workers
Hilary L. Surratt, PhD; James A. Inciardi, PhD; Steven P. Kurtz, PhD
September/October 2006; pages 283-289

Abstract
National population surveys and individual studies over the past decade have documented the escalating abuse of a variety of prescription medications, particularly prescription opioids. Although surveillance data provide important information for estimating the prevalence of prescription opioid abuse in the general population, studies documenting the patterns of prescription drug abuse among chronic street-drug-using populations are extremely rare. This paper examines the abuse of prescription opioids among drug-involved street-based sex workers in Miami, Florida. The data for this study were drawn from an ongoing HIV intervention trial initiated in 2001, designed to test the relative effectiveness of two alternative HIV prevention protocols for this population. Participants in the study were recruited through traditional targeted sampling strategies, and complete data are available on 588 street-based sex workers. In terms of prescription drug abuse, 12.2 percent of the sample reported using at least one opioid analgesic in the past 90 days without having a legitimate prescription. Logistic regression analyses were conducted to examine the associations between prescription opioid abuse and its predictors. In the multivariate model, factors positively associated with prescription opioid abuse included: Caucasian race (OR = 2.53; 95 percent CI 1.30 to 4.91), current powder cocaine use (OR = 2.28; 95 percent CI 1.28 to 4.08), current heroin use (OR = 2.08; 95 percent CI 1.10 to 3.92), 90-day physical abuse/victimization (OR = 2.07; 95 percent CI 1.18 to 3.61), and shorter sex-work involvement (OR = 1.98; 95 percent CI 1.13 to 3.48). In contrast, daily crack smoking was negatively associated with prescription opioid abuse (OR = 0.61; 95 percent CI 0.33 to 1.10). This study provides some of the first empirical evidence to indicate that prescription opioid abuse is emerging in a heretofore unstudied community of marginalized drug-using sex workers. In addition, data on this population’s mechanisms of access to prescription opioids clearly suggest that there is an active black market for these drugs. These findings warrant intensive study to determine the relative contribution of each mechanism of diversion to the illicit market. Key words: opioids, substance abuse, diversion, sex workers


Article
Interpleural bupivacaine and intravenous oxycodone for pain treatment after thoracotomy in children
Hannu Kokki, MD, PhD; Merja Laisalmi, MD; Kari Vanamo, MD, PhD
September/October 2006; pages 290-294

Abstract
Introduction: The results of studies exploring the efficacy of interpleural analgesia in children post-thoracotomy have frequently been inconclusive. In this pilot study, we have evaluated the efficacy and safety of interpleural bupivacaine and intravenous (IV) oxycodone in pain treatment after thoracotomy in 10 generally healthy children, aged 10 months to 12 years, with patent ductus arteriosus who underwent thoracotomy. Methods: After surgery, all 10 children were given ibuprofen 10 mg/kg rectally every six hours. The first dose of interpleural bupivacaine (2 mg/kg) was given with epinephrine at the end of surgery, and thereafter plain bupivacaine (1 mg/kg) was given every two hours if the pain score was 4 or higher on an 11-point numeric rating scale (0 = no pain, 10 = worst possible pain). For rescue analgesia, children were provided oxycodone 0.1 mg/kg IV if pain was not relieved sufficiently with ibuprofen and bupivacaine. Vital signs, pain scores, and all adverse effects were monitored continuously for 24 hours. Results: All 10 children needed both interpleural bupivacaine and IV oxycodone. The number of bupivacaine doses ranged between three and 10 (mean = 6.1, SD = 2.3), and the number of oxycodone doses ranged between one and 12 (mean = 6.0, SD = 3.6). No cases of low respiratory rate or low peripheral oxygen saturation or any serious adverse events were recorded. Conclusion: Scheduled nonopioid analgesic (ibuprofen) with interpleural bupivacaine did not provide sufficient analgesia for post-thoracotomy pain in young children. IV oxycodone was found to be an effective and safe opioid supplement to the pain regimen. Key words: oxycodone, intravenous, bupivacaine, interpleural, ibuprofen, rectal, thoracotomy, pain, child


Article
Literature review. Ultra-low-dose opioid antagonists to enhance opioid analgesia
Paul Sloan, MD; Scott Hamann, PhD, MD
September/October 2006; pages 295-304

Abstract
This article will review decades of science contributing to current interest in opioid excitatory pharmacology. A long history of clinical confusion provided the stimulus for recent, detailed in vivo and in vitro investigations of the neuropharmacologic mechanisms involved in analgesic and hyperalgesic actions of opioid agonists and antagonists. Following the discovery of central nervous system opioid excitatory-hyperalgesic processes in animals, detailed neuronal cell culture experiments established opioid receptor/G protein/adenylate cyclase neurobiochemical mechanisms for bimodal inhibitory versus excitatory actions of opioids. Once this novel model was available to explain the cellular mechanisms responsible for the duality of opioid actions, clinical translation of this technology began to emerge, with a primary focus on selective antagonism of opioid excitatory actions with concomitant low-dose opioid antagonists. Encouraging results from recent animal and clinical studies will be discussed as further evidence that therapeutic pain management may be improved through enhancement of opioid agonist analgesia by cotreatment with ultra-low-dose opioid antagonists that selectively attenuate opioid-mediated hyperalgesia. Key words: chronic pain, opioid agonists, opioid antagonists, adjuvant analgesics, cancer pain, hyperalgesia, analgesia

Journal of Opioid Management
November/December 2006, Volume 2
, Number 6


Article
Looking ahead to 2007
Robert E. Enck, MD
November/December 2006; pages 309-309


Article
Guest editorial. Healthcare professionals and the DEA: Restoring the balance
Howard A. Heit, MD, FACP, FASAM
November/December 2006; pages 310-311


Article
Legal perspective. Science at the mercy of the mob: Dr. Hurwitz’s legal problems in perspective
Siobhan Reynolds, MA, MFA
November/December 2006; pages 312-313


Article
Pharmacy perspective. A patient-activated iontophoretic transdermal system for acute pain management with fentanyl hydrochloride: Overview and applications
Kevin T. Bain, PharmD, BCPS, CGP, FASCP
November/December 2006; pages 314-324

Abstract
Opioid administration by patient-controlled analgesia (PCA) is the standard therapy for acute postoperative pain. Despite its utility in this setting, limitations of this modality do exist. Consequently, noninvasive PCA systems, including an iontophoretic transdermal system (ITS) with fentanyl hydrochloride, are under development to circumvent many of these limitations. This preprogrammed, self-contained, compact, needle-free system provides pain control superior to that of placebo and comparable to morphine PCA in the first 24 hours after major surgical procedures. The objectives of this article are to describe the method of transdermal iontophoretic medication administration and to review the literature pertaining to the fentanyl ITS. Key words: iontophoresis, transdermal, fentanyl, opioid analgesics, patient-controlled analgesia, noninvasive method, postoperative pain, acute pain, breakthrough pain


Article
A randomized, open-label study of once-a-day AVINZA® (morphine sulfate extended-release capsules) versus twice-a-day OxyContin® (oxycodone hydrochloride controlled-release tablets) for chronic low back pain: The extension phase of the ACTION trial
Richard L. Rauck, MD; Stephen A. Bookbinder, MD; Timothy R. Bunker, MD; Christopher D. Alftine, MD; Richard Ghalie, MD; Andres Negro-Vilar, MD, PhD; Egbert de Jong, MD; Steven Gershon, MD
November/December 2006; pages 325-333

Abstract
Study design and objective: The ACTION® trial, an open-label, randomized, multicenter, two-part study, compared the efficacy and safety of two sustained-release opioids (SROs), AVINZA (A-MQD), morphine sulfate extended-release capsules given once a day, and OxyContin® (O-ER), oxycodone modified-release tablets given twice a day, in subjects with chronic, moderate to severe low back pain. The first part of the study, the evaluation phase, was followed by an optional four-month extension phase aimed at evaluating the long-term stability of pain control, SRO dose, and quality of sleep. Results: Three hundred and ninety-two subjects were enrolled in the study; 220 completed the evaluation phase, and 174 entered the extension phase. During the latter phase, subjects in the A-MQD group (n = 79) continued to report lower pain scores, better quality of sleep, lower daily morphine-equivalent doses (means of 86 mg versus 119 mg), and a comparable usage of ibuprofen compared to subjects in the O-ER group (n = 95). The incidence and severity of elicited opioid side effects were similar between the two groups. Conclusions: Both study drugs resulted in significant pain relief and improved sleep in SRO-naive patients with chronic low back pain, and this outcome was attained with a stable daily SRO dose. In patients who completed opioid dose titration, AVINZA performed significantly better than OxyContin in reducing pain scores and improving sleep—with a lower morphine-equivalent daily dose—during both the evaluation and extension phases.


Article
Determinants of variation in analgesic and opioid prescribing practice in an emergency department
Alan Heins, MD; Marianthe Grammas, BS; Janet Kaye Heins, RN, MSN, CRNP; Melissa W. Costello, MD; Kun Huang, MS; Satya Mishra, PhD
November/December 2006; pages 335-340

Abstract
Objective: Adequate treatment of patients’ pain is a top priority for the World Health Organization (WHO), American Medical Association (AMA), and American College of Emergency Physicians (ACEP), but “adequate” is not clearly defined. Most previous studies of emergency department (ED) pain treatments have centered on musculoskeletal pain in terms of rates of analgesia and disparities in treatment based on race and age. This study will examine complaints of pain other than musculoskeletal and will focus on treatment disparities that may result from differences in patient and physician characteristics. Methods: This retrospective study is of ED patients 18 years and older with nonmusculoskeletal pain who were seen by ED faculty over a period of eight weeks. Logistic regression and c2 tests were performed to quantify effects of doctor, patient, and clinical characteristics on rates of ED analgesia, ED opioids, and analgesic prescriptions at discharge. Results: A total of 1,360 patients were included. There was wide variation in the type and frequency of ED analgesia depending on the attending doctor. For example, patients seen by one specific ED doctor were less than half as likely to receive any analgesia and seven times less likely to receive an opioid than those seen by another doctor. Age, race, doctor’s training and experience, and whether the patient had chronic pain were important predictors of ED analgesia. There were similar findings for ED opioids and discharge analgesics. Conclusion: Pain practices in EDs are highly variable and seem inadequate when measured against the goals of WHO, AMA, and ACEP. Patient age, race, and type of pain and the physician’s identity, training, and experience all contribute to practice variation. Further research is needed to identify the causes of these variations, and there is a need to develop interventions to standardize and improve pain assessment and treatment. Key words: emergency department, pain, pain management, analgesics, opioids


Article
Linkage to methadone treatment from acute opiate detoxification treatment
Nickolas D. Zaller, PhD; Portia Thurmond, MPH; Jon Brett, PhD; James C. Carleton, MS; Josiah D. Rich, MD, MPH
November/December 2006; pages 341-346

Abstract
Methadone maintenance treatment (MMT) is a safe pharmacological treatment strategy for addiction to heroin and other opiates; however, linking individuals to MMT is often challenging. We present results from a pilot project (Project VISTA) funded by the Center for Substance Abuse Treatment that helps heroin-dependent injection drug users (IDUs) transition from acute heroin detoxification to MMT. Participants are referred to Project VISTA by the state detoxification center, and Project VISTA facilitates entry into an MMT program, providing full financial support for up to 24 weeks. In addition, Project VISTA provides case management and referral to ancillary services such as housing, other medical care, and mental health treatment. From May 2005 to May 2006, 60 individuals were enrolled in Project VISTA. A total of 41 participants (69.5 percent) remained in treatment for at least 24 weeks, with a mean number of weeks in treatment of 31. A Kaplan-Meier analysis was performed on all participants, and the incidence of individuals being discharged from treatment was 2 percent per week. Project VISTA, in cooperation with the state detoxification center and a Providence-based MMT program, has created a model that provides continuity of treatment services to high-risk, HIV-negative IDUs. Our model demonstrates that through facilitating the transition from an opiate detoxification program into an MMT program, individuals with chronic heroin addiction can successfully access and engage in treatment. Key words: methadone maintenance treatment, injection drug users, detox, HIV prevention


Article
Breakthrough pain in opioid-treated patients with neuropathic pain
Steve Simon, MD, RPh; Daniel S. Bennett, MD; Richard Rauck, MD; Donald Taylor, MD; Steven Shoemaker, MD
November/December 2006; pages 347-352

Abstract
Objective: This report aims to describe the prevalence and characteristics of breakthrough pain in patients with neuropathic pain. Methods: The study represents data from a subset of patients from a larger survey of 228 patients with chronic noncancer pain. Patients were identified from nine pain programs and were administered a telephone questionnaire. The study population comprised 45 chronic noncancer pain patients with primary neuropathic pain diagnoses who were being treated with opioids. Results: Pain had been present for a median of six years. Medications used for pain in addition to opioids included nonsteroidal anti-inflammatory agents (29 percent), antidepressants (60 percent), and anticonvulsants (53 percent). Thirty-five of the patients (78 percent) described a total of 42 distinct types of breakthrough pain. The median number of episodes per day was two; the median time to maximum intensity was 10 minutes, and the median duration of pain was 60 minutes. Patients could identify a precipitant for 62 percent of the pains, and 88 percent of the precipitants were activity related. The onset of breakthrough pain could not be predicted for 48 percent of the pains and could only sometimes be predicted for 29 percent of the pains. Conclusion: Breakthrough pain is common in opioid-treated patients with chronic neuropathic pain. Such pain often has a rapid onset and a relatively short duration, and it is frequently difficult to predict, similar to breakthrough pain in cancer patients. Key words: breakthrough pain, chronic pain, neuropathic pain, survey


Article
Literature review. Perioperative management of opioid-tolerant chronic pain patients
Dima Rozen, MD; Noah P. DeGaetano, MD
November/December 2006; pages 353-363

Abstract
Opioids occupy a position of unsurpassed clinical utility in the treatment of many types of painful conditions. In recent years there has been a noticeable shift regarding the use of opioids for the treatment of both benign and malignancy-related pain. As acceptance of the prescribing of opioids for chronically painful conditions has grown, many more opioid-tolerant patients are presenting for surgical procedures. It is therefore imperative that practicing anesthesiologists become familiar with currently available opioid formulations, including data regarding drug interactions and side effects, in order to better plan for patients’ perioperative anesthetic needs and management. Unfortunately, there is a lack of scientifically rigorous studies in this important area, and most information must be derived from anecdotal reports and the personal experience of anesthesiologists working in this field. In this review, we shall discuss current chronic pain management and the impact of opioid use and tolerance on perioperative anesthetic management. Key words: opioids, opioid tolerance, chronic pain, perioperative, anesthesia


Article
Case study. Safety and tolerability of high doses of intrathecal fentanyl for the treatment of chronic pain
Sulane Do Ouro, MD; Santiago Esteban, BS; Una Sibirceva, MD; Beverly Whittenberg, MD; Russell Portenoy, MD; Ricardo A. Cruciani, MD, PhD
November/December 2006; pages 365-368

Abstract
Fentanyl is commonly used systemically or neuraxially for the management of chronic pain. It can be administered intrathecally via implanted pump, but it is generally considered only after trials of intrathecal (IT) morphine and hydromorphone have proven ineffective. Published experience with IT fentanyl is limited, and long-term therapy at relatively high doses has not been described previously. We describe four patients who were treated with IT fentanyl after other analgesic approaches had failed and who gradually underwent dose escalation to levels as high as 20 times those previously reported. Safety and tolerability were maintained during dose titration. Our experience highlights an expanding scope of practice in the use of IT opioids in general and fentanyl specifically and suggests that high-dose fentanyl can be used safely in highly selected patients. Key words: fentanyl, intrathecal, dose escalation, chronic pain