Fentanyl Patch Research Articles

Comparative study between transdermal fentanyl and melatonin patches on postoperative pain relief after lumber laminectomy, a double-blind, placebo-controlled trial

BackgroundThis study evaluated the efficacy of transdermal fentanyl (TDF) delivery system (50 μg/h) or transdermal melatonin (TDM) delivery system (7 mg) 2 h preoperatively for acute postoperative pain after lumbar laminectomy compared to placebo group (C).MethodsSeventy-five patients of both sexes, aged 18–50 years, ASA I and II undergoing elective single level lumber laminectomy under general anesthesia were included in this randomized controlled double-blind study. Patients were randomly divided into 3 groups 25 each, C group patients received transdermal placebo patch, TDF group (50 μg/h) and TDM group (7 mg). Assessment of postoperative pain, sedation, hemodynamic variables such as HR and MAP, postoperative monitoring of arterial SpO2 and side effects (e.g. nausea, vomiting, pruritis, respiratory depression and hemodynamic instability) was done 30 min, 1, 2, 6 and 12 h postoperatively. Postoperative Patient‘s and Surgeons‘ satisfaction, Intraoperative bleeding and plasma cortisol (μg/dl) postoperatively were also assessed.ResultsThere was a significant reduction in the VAS score, total pethidine requirements and significantly higher Patient‘s satisfaction in TDF and TDM groups when compared with the C group 6 h postoperatively. The sedation score and Surgeons‘ satisfaction were significantly higher associated with a significant decrease in MAP and Intraoperative bleeding in TDM group compared to groups C and TDF 6 h postoperatively. Significant nausea and vomiting in TDF group and significant sedation in TDM group were recorded.ConclusionThe use of preoperative TDF 50 μg/h or TDM 7 mg was an effective and a safe adjuvant for acute pain after surgery.

Postoperative Pain Control with the Fentanyl Patch and Continuous Paravertebral Anesthetic Infusion after Posterior Occipitocervical Junction Surgery.

Postoperative pain is a significant concern for patients who undergo surgery via a midline posterior approach to the occipitocervical junction and spinal axis. The development of the disposable, ambulatory pain pump presents a novel alternative for treatment of postoperative pain. The authors describe a multimodal treatment algorithm for postoperative pain after posterior occipitocervical junction surgery that uses the On-Q pain catheter system (I-Flow Corp., Lake Forest, CA) and a fentanyl patch.The On-Q PainBuster catheter system is a disposable, ambulatory device that allows for continuous anesthetic delivery directly into or adjacent to the wound. On-Q catheters are placed in the nuchal musculature for continuous infusion of 0.5% bupivacaine. The On-Q catheter infusion is continued for three days, and the catheters are then withdrawn. Patients are also provided with a transdermal fentanyl patch at the start of surgery.In regards to complications at our facility, there have been no cases of respiratory depression or arrest postoperatively and no wound infections, but one case of inadvertent subdural placement.The technique described for the use of the fentanyl patch and a continuous anesthetic delivery device in surgery of the occipitocervical junction presents a novel alternative to the current standard of care in pain control after suboccipital decompression.

Use of Fentanyl Patch for Treatment of Moderate-to-severe Chronic Noncancer Pain: Postmarketing Surveillance of Medical Practice in Japan Using a Risk Minimization Action Plan.

The purpose of this study was to discuss the safety, treatment profile, and clinical effectiveness of 12-month treatment with fentanyl patch (FP), a strong opioid, in medical practice in Japan under the risk minimization action plan (RMAP). Patients with moderate-to-severe chronic noncancer pain who had switched to FP from another opioid were registered to take this survey to assess adverse drug reactions (ADRs), therapeutic effect, and pain intensity for up to 12 months. A total of 517 patients were enrolled, and 499 patients (male, 50.9%; mean [SD] age, 63.0 [15.4] years) were included in the safety population. During the 12-month observation period, an ADR occurred in 262 patients (52.5%); most frequent ADRs included nausea (24.2%), somnolence (22.4%), constipation (18.2%), vomiting (9%), and dizziness (4.6%). The prespecified priority survey items, including respiratory depression, drug dependence, and drug withdrawal syndrome, occurred in 2 (both nonserious), 3 (all serious), and 9 (all serious) patients, respectively. In 418 patients from the efficacy population, the response rate was 77.3%, the rate of achievement of the therapeutic goal was 64.5%, and the visual analog scale (VAS) scores for pain severity decreased by 22.3 (26.9) mm. Our results identified a reasonable risk-benefit profile for the management of moderate-to-severe chronic noncancer pain in patients previously treated with opioids under long-term treatment with FP under the RMAP. Respiratory depression, drug dependency, and drug withdrawal were rarely observed even under the RMAP in Japan.

Safety of fentanyl initiation according to past opioid exposure among patients newly prescribed fentanyl patches

Although a convenient opioid delivery system, transdermal fentanyl patches have caused several deaths and resulted in safety warnings reminding prescribers that fentanyl patches should be prescribed only for patients who have adequate prior exposure to opioids. We conducted a longitudinal analysis of the safety of fentanyl initiation by examining past opioid exposure among patients newly prescribed fentanyl patches. We identified all patients in the province of Manitoba who were newly prescribed fentanyl patches between Apr. 1, 2001, and Mar. 31, 2013. We converted all prior opioid use to oral morphine equivalents and determined the average daily dose in the 7-30 days before initial fentanyl patch use. Fentanyl initiation was considered unsafe if the patient's pre-fentanyl opioid exposure was below the recommended level. We identified 11 063 patients who began using fentanyl patches during the study period. Overall, fentanyl initiation was deemed unsafe in 74.1% of cases because the patient's prior opioid exposure was inadequate. Women and patients 65 years of age and older were more likely than men and younger patients, respectively, to have inadequate prior opioid exposure (p < 0.001 for each comparison). The proportion of patients who had unsafe prescriptions for fentanyl patches decreased significantly over the study period, from 87.0% in 2001 to 50.0% in 2012 (p < 0.001). The safety of fentanyl initiation improved over the study period, but still half of fentanyl patch prescriptions were written for patients with inadequate prior opioid exposure. Review of prior opioid exposure may be a simple but important way to improve the safe use of fentanyl patches.

Could chest wall rigidity be a factor in rapid death from illicit fentanyl abuse?

Background: There has been a significant spike in fentanyl-related deaths from illicit fentanyl supplied via the heroin trade. Past fentanyl access was primarily oral or dermal via prescription fentanyl patch diversion. One factor potentially driving this increase in fatalities is the change in route of administration. Rapid intravenous (IV) fentanyl can produce chest wall rigidity. We evaluated post-mortem fentanyl and norfentanyl concentrations in a recent surge of lethal fentanyl intoxications. Methods: Fentanyl related deaths from the Franklin County coroner’s office from January to September 2015 were identified. Presumptive positive fentanyl results were confirmed by quantitative analysis using liquid chromatography tandem mass spectrometry (LC/MS/MS) and were able to quantify fentanyl, norfentanyl, alfentanyl, and sufentanyl. Results: 48 fentanyl deaths were identified. Mean fentanyl concentrations were 12.5 ng/ml, (range 0.5 ng/ml to >40 ng/ml). Mean norfentanyl concentrations were 1.9 ng/ml (range none detected to 8.3 ng/ml). No appreciable concentrations of norfentanyl could be detected in 20 of 48 cases (42%) and were less than 1 ng/ml in 25 cases (52%). Elevated fentanyl concentrations did not correlate with rises in norfentanyl levels. In several cases fentanyl concentrations were strikingly high (22 ng/ml and 20 ng/ml) with no norfentanyl detected. Discussion: The lack of any measurable norfentanyl in half of our cases suggests a very rapid death, consistent with acute chest rigidity. An alternate explanation could be a dose-related rapid onset of respiratory arrest. Deaths occurred with low levels of fentanyl in the therapeutic range (1–2 ng/ml) in apparent non-naïve opiate abusers. Acute chest wall rigidity is a well-recognized complication in the medical community but unknown within the drug abuse community. The average abuser of illicit opioids may be unaware of the increasing fentanyl content of their illicit opioid purchase. Conclusion: In summary we believe sudden onset chest wall rigidity may be a significant and previously unreported factor leading to an increased mortality, from illicit IV fentanyl use. Fentanyl and norfentanyl ratios and concentrations suggest a more rapid onset of death given the finding of fentanyl without norfentanyl in many of the fatalities. Chest wall rigidity may help explain the cause of death in these instances, in contrast to the typical opioid-related overdose deaths. Intravenous heroin users should be educated regarding this potentially fatal complication given the increasingly common substitution and combination with heroin of fentanyl.

Analysis of the Abuse and Diversion of the Buprenorphine Transdermal Delivery System.

Prescription opioid abuse and diversion are major causes of morbidity and mortality in the United States. The buprenorphine transdermal delivery system (BTDS) is indicated for the treatment of moderate to severe chronic pain and provides a continuous dose of 5, 7.5, 10, 15, or 20μg/h buprenorphine for 7days. Quarterly rates of abuse and diversion of BTDS were compared with 4 comparator groups: 1) other buprenorphine products, 2) fentanyl patches, 3) extended-release (ER) opioid tablets/capsules, and 4) ER tramadol. Data were obtained from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) System Poison Center, Drug Diversion, Treatment Programs Combined (Opioid Treatment and Survey of Key Informants' Patients Programs), and College Survey Programs. Rates were calculated using case counts per population and mentions per prescriptions filled. Poisson regression analysis was used to compare mean rates over time across drug groups after allowing for drug group-specific dispersion parameters. Population adjusted abuse rates were low for BTDS in all of the RADARS System programs compared with the other comparator groups. Findings were similar for the prescription adjusted rates, with BTDS reported at the lowest rates in all programs. Route of abuse differed slightly for BTDS and the comparator groups depending on the program. BTDS was abused and diverted at low rates compared with the other opioid groups in 5 programs of the RADARS System using either population-based rates or prescription dispensed rates. Data from the RADARS System show the BTDS is abused and diverted at low rates compared with other opioid groups including other forms of buprenorphine, fentanyl patches, ER opioid formulations, and ER tramadol.

Paroxysmal sympathetic hyperactivity in brainstem-compressing huge benign tumors: clinical experiences and literature review.

Severe paroxysmal sympathetic overactivity occurs in a subgroup of patients with acquired brain injuries including traumatic brain injury, hypoxia, infection and tumor-related complications. This condition is characterized by sudden increase of heart rate, respiratory rate, blood pressure, body temperature and excessive diaphoresis. The episodes may be induced by external stimulation or may occur spontaneously. Frequent occurrence of this condition could result in secondary morbidities, therefore, should be diagnosed and managed insightfully. These symptoms could be confused with seizures or other medical conditions, leading to unnecessary treatment. Despite clinical significance of paroxysmal sympathetic hyperactivity (PSH), brain tumor-induced PSH has not been studied nearly. In this report, two cases of the PSH in patients with brainstem-compressing benign tumors were introduced. The most useful pharmacologic agents were opioid (e.g., fentanyl patch) in preventing PSH attack, and nonselective β-blocker (e.g., propranolol) in relieving the symptoms. Clinical experiences of the rare cases of benign tumor-induced PSH can be helpful as an essential basis for further research.

Drug use evaluation of transdermal fentanyl in a tertiary hospital

ObjectivesThe primary objective of the study was to assess the rationale of fentanyl patch initiation and continuation for pain. The secondary objectives were to analyse prescribing pattern between disciplines, monitoring...

A rapid, simple and sensitive method for the determination and bioequivalence study of transdermal fentanyl in human plasma using liquid chromatography-electrospray ionization tandem mass spectrometry.

Since the 1960s, fentanyl has been used to replace morphine nd other opioids due to its higher potency in the treatment of acute pain; since the 1990s, it has also been administrated to control chronic pain by using transdermal fentanyl device system. It is crucial and of utmost importance and crucial to validate a sensitive method for the quantification of transdermal fentanyl in human plasma. A rapid, simple and sensitive high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method has been established and validated for the determination of transdermal fentanyl in human plasma using fentanyl-D5 as an internal standard (IS). Following liquid-liquid extraction (LLE) with n-hexane, the extracts were separated on a Thermo Hypersil ODS(C18) column (2.1 × 150 mm i.d., 5 μm) interfaced with a triple-quadrupole tandem mass spectrometer using positive electrospray ionization. Quantification of fentanyl was carried out by multiple reaction monitoring (MRM) of the transitions at m/z 337.1→188.0 for fentanyl and 341.9→187.9 for IS. The lower limit of quantification was 9.75 pg×mL-1, and the test showed a linear range of 9.75 - 10,000 pg×mL-1. The validated method was subsequently applied to a bioequivalence (BE) study in 24 healthy Chinese volunteers by using transdermal fentanyl patches.

Double blind randomized comparative study of transdermal fentanyl patch for post operative pain relief in major abdominal surgery as a component of multimodal analgesic therapy

Background: There are various methods of alleviating post-operative pain, multimodal analgesia is the recommended practice. Fentanyl patch can also be used in the management of acute postoperative pain. We have done a study to compare the efficacy of fentanyl patch to a placebo patch as a part of multimodal analgesic strategy. Methods: Forty four patients were randomized into two groups. Groups were named as FP (Fentanyl patch) and P (Placebo). The Patch was placed 10-12 hours before surgery and patient was monitored for 72 hours postoperatively for pain by NRS (Numeric Rating Scale). All the patients received regular Paracetamol and Diclofenac Sodium. Tramadol was given as rescue analgesia if the NRS scale was more than 5. Data was analysed using Windows stat version 9.2 from Indostat services. Results: There was statistically significant difference in the consumption of Tramadol in patients with FP group (19.44 mg) as compared to P group (72.22mg) over 72 hours. The Numerical Rating scale was also much lower in the FP group at 8, 16, 24, 32, 40, 48, 56, 64 and 72 hours. Maximum difference in the pain score being at 24 hours for the FP group. No difference in the Sedation, Pruritus, Respiratory depression, Nausea and vomiting scores in the two groups. Conclusions: Transdermal Fentanyl Patch of 25 µg/hr when applied 10-12 hours before surgery provides effective postoperative pain relief after major abdominal surgery as a part of multimodal analgesia.

Postspinal analgesic effect of transdermal fentanyl patch (2.5 mg and 5 mg) in abdominal hysterectomy: A randomized double-blind control study

Background and Aims: The use of transdermal patches to deliver drugs systemically for postoperative analgesia offers lots of pharmacological and nonpharmacological advantages over the conventional enteral and parenteral drug therapies. Aim of this study was to assess the difference in mean duration and quality of postspinal analgesia in patients underwent elective abdominal hysterectomy. Methods: Sixty patients of American Society of Anesthesiologists Grade I and II undergoing elective abdominal hysterectomy were randomized into three groups of 20 each using chit in box method (Group I control, Group II 2.5 mg fentanyl patch, and Group III 5 mg fentanyl patch). The ANOVA test and post hoc test were used for continuous data and Chi-square test was used for count data. Results: The mean difference of visual analog scale score were significantly low in Group III and Group II (P = 0.00). The mean total duration of analgesia was more in Group III and Group II (P = 0.00). The requirement of rescue analgesic dose was significantly low in Group II and no rescue analgesic needed in Group III (P = 0.00). No significant side effects were noted. Conclusions: Transdermal fentanyl patch (TFP) (50 mcg/h) provides better postoperative analgesia than TFP (25 mcg/h) and placebo patch with significant reduction of requirement of rescue analgesic dose.

Pain May Lead to Malnutrition in Nursing Home Patients

Pain may be a factor in malnutrition in nursing home residents, according to a recent study published in Clinical Nutrition. The report points to a need for prompt assessment and treatment of pain to prevent appetite loss in this population, and consideration of the nutritional impact of drugs when selecting analgesics. In an analysis of data on individuals in 12 nursing homes, Austrian researchers looked at relationships between pain, appetite, and other factors that may have influenced malnutrition. The population assessed, in a secondary analysis from the OSiA (Optimiertes Schmerzmanagement in Altenpflegeheimen, or “optimized pain management in nursing homes”) Study, was 243 nursing home residents 60 or older who had mild or no cognitive impairment (Clin Nutr 2015;34[Suppl 1]:557). Baseline information was drawn from standardized questionnaires and medical documentation. Pain was detected with a verbal rating scale, and a Simplified Nutritional Appetite Questionnaire (SNAQ) was used to detect risk of malnutrition in the patients. A SNAQ score of at least 14 indicates that an individual is at risk of weight loss of at least 5% in the next 6 months. Cross-sectional and single-case analyses showed that overall, 66% of the nursing home residents had pain at rest or in action, 22% had no appetite because of pain, and 25% were at risk of malnourishment. Of the patients in the latter group, 30% reported pain. Pain was reported as the cause of loss of appetite by 43% of those who were at risk for both malnutrition and pain. Looking at use of analgesics in the population, the authors found that 64% of patients at risk of malnutrition, pain, and pain-associated loss of appetite were given analgesics with known adverse effects that included appetite loss, nausea, and vomiting. The drugs in this “inadequate” category that were most commonly prescribed were oral hydromorphone and transdermal fentanyl, and they were given in higher quantity than other drugs. The diagnoses that triggered use of analgesics in the study population included disorders of spine/extremities, injuries, arthrosis, and gastritis/gastralgia, and did not differ whether treatment was considered adequate or inadequate. There were also no differences in use of additional analgesics, such as local diclofenac and oral metamizol (also known as dipyrone, a non-NSAID analgesic and antipyretic not available in the United States), in patients on hydromorphone or fentanyl vs. other pain medications. Presenting the results at the 37th Congress of the European Society for Clinical Nutrition and Metabolism in Lisbon, Portugal, Maria Magdalena Schreier of the Institut of Nursing Science and Practice at Paracelsus Medical University said that screening and assessment of malnutrition should consider pain as a favoring factor for poor appetite. “Nearly two-thirds of the selected residents received analgesics with nutritional side effects. Those analgesics may play an important role in the context of malnutrition.” She encouraged clinicians caring for nursing home residents to assess them for pain systematically and to provide adequate pain treatment to prevent malnourishment in these patients. The appetite-reducing potential of drugs, too, should be considered. Judith M. Orvos, ELS, is a freelance medical writer and president of Orvos Communications in Washington, DC. In this study, 243 residents 60 years or older with no or mild cognitive impairment from 12 nursing homes were screened for pain and assessed for appetite using SNAQ (Short Nutritional Assessment Questionnaire). The results of this study indicated that pain was reported as the cause of loss of appetite by 43% of residents at risk for both malnutrition and pain. Additionally, the researchers investigated the use of analgesics in this population and reported that some of the medications used for pain — oral hydromorphone and fentanyl patches — caused side effects including appetite loss, nausea, and vomiting. The researchers concluded that pain should be evaluated for all nursing home residents using a systematic pain assessment tool and that analgesics provided should be considered for potential nutritional side effects. This study validates and quantifies the impact of pain as a risk factor for malnutrition in older adults in long-term care. In addition to other physical causes of malnutrition including impaired oral status, physical limitations, chronic disease, early satiety, and changes in taste and smell, the presence of pain should be considered when evaluating a resident's risk for malnutrition. Although medications can be helpful to control pain, there are potential side effects of medications which can have negative impacts on nutrition status, including loss of appetite, nausea, vomiting, and constipation, among others. An interdisciplinary approach including the physician, registered nurse, and dietitian should be considered when evaluating and treating pain in the institutionalized older adult. —Phyllis Famularo, DCN, RD Senior Manager, Nutrition Services, Sodexo

Entropy-guided use of a unique cocktail in awake craniotomy

The major benefit of awake craniotomy is to enable a tailored resection that can theoretically maximize the extent of the tumor resection and can minimize the neurological damages. There is still no consensus as to the best anesthetic technique. We describe here a case report where a combination of propofol infusion and dexmedetomidine along with intermittent doses of fentanyl, and fentanyl patch was used with entropy monitoring to assess the depth of sedation in a patient for awake craniotomy.

Efficacy of fentanyl transdermal patch in pain control after lower third molar surgery: A preliminary study.

BackgroundSurgical removal of impacted lower third molars is a common oral surgical procedure, generally followed by moderate to severe postoperative pain. Transdermal drug delivery as a concept offers interesting possibilities for postoperative pain control. The aim of this study was to evaluate the efficacy of transdermal system with fentanyl in relieving pain following impacted lower third molar surgery.Material and MethodsSeventeen patients with bilateral impacted lower third molars were included in this preliminary study. For postoperative pain control, patients randomly received a fentanyl patch plus placebo tablet after the first operation and regular (placebo) patch and an analgesic, after the second operation. Analgesia was evaluated during first 24 hours postoperatively according to patients’ reports about time of first pain appearance and additional analgesic consumption. Pain severity was rated using a 10 cm long visual analogue scale (VAS).ResultsIntensity of postoperative pain and postoperative analgesic consumption were significantly lower after the Fentanyl Transdermal System (FTS) was applied (p<0.05). Duration of postoperative analgesia was significantly higher with FTS when compared to control treatment (p<0.05).ConclusionsBased on the results of this preliminary study, transdermal system with fentanyl significantly reduced postoperative pain after third molar surgery. Key words:Analgesia, fentanyl, transdermal administration, third molar surgery, acute pain, postoperative care.

Successful treatment by transdermal fentanyl patch for intractable chronic lumbar back pain

Successful treatment by transdermal fentanyl patch for intractable chronic lumbar back pain

Fentanyl related cases. The situation in Greece

Objective: Fentanyl is used as a pre-anesthetic medication and it is also prescribed for the management of chronic pain through the delivery method of transdermal patches. It is used or abused, as a recreational drug, worldwide. As a result, a significant number of fentanyl related deaths have been recorded in many countries, as well as in Greece. The aim of this paper is to present the current situation in Greece through the report of specific fentanyl related cases and to discuss the different aspects of fentanyl abuse. Methods: A gas chromatography-mass spectrometric method was developed, validated and applied for the determination of fentanyl in biological fluids during the investigation of fentanyl related cases. Results: Eight cases, lethal or not, have been recorded the last four years in Greece, where fentanyl blood concentration was found up to 22.7 ng/mL. Five of the cases concerned therapeutic use of fentanyl and three were related to abuse of the drug. Furthermore, six of these cases concerned fentanyl transdermal patches. Conclusions: The commercial success of transdermal fentanyl is impressive and ensures that the drug will remain in market for years to come. The litigation surrounding the use and abuse of fentanyl patches is a major concern today. Warning and information to users and practitioners about the possibility of adverse effects, even death, law enforcement action, prescribing regulations, and availability of rapid and accurate analytical methods for the determination of fentanyl in biological specimens, must be under deliberation.

Improving patient safety with fentanyl patches. Time for a renewed focus

Improving patient safety with fentanyl patches. Time for a renewed focus

401P Fentanyl patch is the most common strong opioids in Taiwan cancer patients

401P Fentanyl patch is the most common strong opioids in Taiwan cancer patients

Postoperative Analgesia Provided by Liposomal Hydromorphone in Client-Owned Dogs Undergoing Limb Amputation.

The analgesic efficacy of liposomal hydromorphone (LE-hydro) was tested in dogs undergoing limb amputation. The positive controls (n = 10) received subcutaneous (SQ) hydromorphone (0.2 mg/kg) and 1.5 mL of blank liposomes before surgery; fentanyl continuous rate infusion (CRI), 5-10 μg/kg/hr IV, during and for 24 hr after surgery; and a fentanyl patch at extubation. The negative controls (n = 7) received SQ hydromorphone (0.2 mg/kg) and 1.5 mLs of blank liposomes SQ before surgery, fentanyl CRI (5-10 μg/kg/hr IV) during surgery but stopped at extubation, and a fentanyl patch at extubation. The test group (n = 11) received 3 mg/kg of LE-hydro and 1.5 mL of saline SQ before surgery, 1.5 mL of saline SQ, and a saline CRI during surgery. All groups received a bupivacaine block in the limb prior to amputation and carprofen prior to surgery. Treatment failures, pain scores, opioid side effects, heart rate, respiratory rate, temperature, and client-reported pain and side effects were evaluated. There were three treatment failures in the positive control (3/10) and test groups (3/11). Negative controls had seven treatment failures (7/7). Side effects for all three groups were within expected limits. LE-hydro provides postoperative analgesia equivalent to fentanyl CRI in dogs undergoing limb amputation.

Effectiveness of a Retrospective Drug Utilization Review on Potentially Unsafe Opioid and Central Nervous System Combination Therapy.

Drug overdose deaths are the leading cause of unintentional death in the United States, and opioid-related mortality is the primary contributor (75.2%). Among opioid-related mortalities, opioids are most commonly taken with benzodiazepines (30.1%) and antidepressants (13.4%). The utility of a retrospective drug utilization review (DUR) program initiated by a commercial health plan for members taking potentially unsafe opioid and central nervous system (CNS) combination therapy is currently unknown. To determine the effectiveness of a retrospective DUR program on potentially unsafe opioid and CNS combination therapy. This research is a pre-post study utilizing pharmacy claims data from 2.6 million commercially insured members enrolled in a health plan in the Midwest. Members were required to be at least aged 18 years as of August 30, 2013, and continuously enrolled from May 2, 2013, through February 15, 2014. Members with 1 or more paid claims for an opioid at least 200 morphine equivalent dose (MED) daily and a concur- rent supply of another opioid, benzodiazepine, or antidepressant from May 2, 2013, through August 30, 2013 (120-day preintervention period) were targeted for the retrospective DUR program. These exclusion criteria were applied: members belonging to commercial groups requiring permission on claims data analyses, missing or invalid prescriber information, or presence of pharmacy claims indicating human immunodeficiency virus or acquired immunodeficiency syndrome during the 2 years prior to the pre-intervention period. Prescribers of high-dose opioids received a mailing (intervention) containing a member-specific letter, medication profile, and satisfaction survey to determine the prescriber-perceived clinical value of the program. To assess the effectiveness of the retrospective DUR program, criteria was reapplied to identify members still meeting criteria 120 days postintervention (February 15, 2014). Paired samples t-test was used to compare pre-post results. Of 2,236,243 eligible members aged 18 years and older, 980 met DUR criteria. Prescribers for these members subsequently received a mailing regarding potentially unsafe opioid and CNS combination therapy. A total of 671 prescribers were sent a mailing regarding these 980 members. Among the 980 members meeting DUR criteria, distribution of prescriber specialty was family medicine (25.9%), physical medicine and rehabilitation (14.4%), internal medicine (13.0%), pain (9.2%), anesthesiology (7.0%), other (8.8%), and unknown (21.7%). High-dose opioids most commonly identified by the DUR were oxycodone extended release (27.6%), morphine sulfate extended release (17.7%), and fentanyl patch (13.1%). After reapplying DUR criteria to identify members still meeting criteria 120 days after the DUR, 528 members remained, representing a 28.1% reduction in high-risk opioid use. Survey response rate was 23.6% (231 of 980 surveys returned). The majority (62.3%) of respondents reported that this retrospective DUR program was useful in their daily practice. A 28.1% reduction in potentially unsafe opioid and CNS combination therapy was observed after implementing a retrospective DUR program targeting high-risk opioid use. Among members remaining high risk after the DUR, the change in total unique opioids and total daily MED was nonsignificant. Members remaining at high risk after the DUR can be targeted for further interventions such as care management and member education regarding fraud, waste, and abuse. A majority of prescribers (90.5%) self-report using their states' prescription monitoring programs when prescribing controlled substances.