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November-December 2006; Issue 6Patient Education Can Help Avoid Adverse Drug Reactions This edition of News/Research Updates was researched/compiled by Winnie Dawson, MA, RN, BSN [WD], and edited by Stewart B. Leavitt, MA, PhD [SBL]. Medical reviewers were: James D. Toombs, MD; Lee A. Kral, PharmD, BCPS; Paul W. Lofholm, PharmD, FACA; Steven J. Tucker, MD. Posting Date: December 18, 2006. Patient Education Can Help Avoid Adverse Drug ReactionsBased on the results of a new government study published in the Journal of the American Medical Association in October, it is estimated that up to 700,000 Americans visit a hospital emergency room (ER) each year due to the adverse effects of medications. The investigators recruited 63 hospitals to participate in the National Electronic Injury Surveillance System – Cooperative Adverse Drug Event Surveillance Project covering a 2-year period. A total of approximately 21,000 patients reported adverse drug effects (weighted estimates equaled 700,000 annually nationwide) and represented 2.5% of all ER visits. People aged 65 and older were more than twice as likely to experience an adverse event and even more likely to be hospitalized for the reaction. While medications that require vigilant dosing (such as insulin, digoxin, warfarin, and anticonvulsants) are more likely to cause adverse events, more than 5% of the visits were due to the unwanted effects of nonsteroidal anti-inflammatory drugs (NSAIDs) and other medications for treating musculoskeletal discomfort. Opioid-containing analgesics as a group was one of the 5 most common drug classes reported as associated with adverse drug effects. Clinical Implications: The practice of good patient education regarding the potential adverse effects of prescribed drugs, including unintentional overdosing and drug interactions, can help to reduce these statistics. Additionally, it is important to take a patient history that includes the identification of all over-the-counter (OTC) drugs and supplements in use. Patient age may affect drug metabolism and patients may need help in understanding that some OTC drugs contain the same active ingredient and, when taken together, increase the risk of unintentional overdose. For patient handouts on the drug-drug interactions of common pain relievers and a list of the active ingredients in OTC products, see the Pain-Topics.org Patient Resources item, “Pain Relievers: Understanding Your OTC Options,” available at: http://www.pain-topics.org/patient_resources/index2.php#gppainrel (access checked 12/11/06). – WD. Reference: Budnitz DS, Pollock DA, Weidenbach KN, et al. National surveillance of emergency department visits for outpatient adverse drug events. JAMA. 2006(Oct);296(15):1858-1866. < Back to Top > Suicidal Thoughts Explored in Patients With Chronic PainChronic pain reduces an individual’s quality of life and is known to lead to feelings of helplessness, hopelessness and, ultimately, chronic depression. This study of suicidal ideation explored its relationship to pain-related coping strategies and catastrophizing [pessimistically projecting an undesirable situation or bad events over many realms of life] in patients with chronic pain. A series of questionnaires that assessed the pain experience, psychosocial symptoms, depression, coping strategies, and health behaviors were administered to 1,512 patients who sought treatment for chronic pain. The results of questionnaires indicated that about 32% of participants reported some elements of suicidal ideation. Higher scores on the depression assessment and higher levels of pain-related catastrophizing were the most significant, and consistent, predictors of the presence and degree of suicidal thoughts. The two factors – depression and catastrophizing – interacted to create an additive effect, predicting greater suicidal thoughts than the two variables independently. Surprisingly, severity and duration of pain showed only a moderate association with participants’ thoughts about committing suicide. Practice Perspectives: In a news interview, the lead author stated that his team is interested in studying whether the use of medications to reduce catastrophizing, such as the selective serotonin-norepinephrine reuptake inhibitors (SNRIs), would reduce suicidal thoughts. Meanwhile, this study highlights the importance of early identification of psychological factors that might increase the risk of suicidal ideation, which could ultimately guide suicide prevention interventions. Whenever possible, patient history at intake should include an assessment of depression and identification of the presence of the maladaptive coping strategy of catastrophizing. – WD. Reference: Edwards RR, Smith MT, Kudel I, et al. Pain-related catastrophizing as a risk factor for suicidal ideation in chronic pain. Pain. 2006(Dec 15);126(1-3):272-279. < Back to Top > Methadone Analgesia Dose Remains Stable Over TimeIt has been suggested that during titration and long-term therapy, methadone may induce its own metabolism (autoinduction) and necessitate periodic dose increases. Researchers in Norway (Fredheim et al. 2006) enrolled 12 patients treated with morphine for chronic non-malignant pain and switched them to methadone during a 3-day period. Morphine doses were reduced by 1/3 each day and substituted with a daily increase of 1/3 of the equianalgesic methadone dose. Morphine-to-methadone dose conversion ratios of 4:1 and 6:1 were applied for baseline morphine doses of <200 mg/d and >200 mg/d, respectively. After titration, methadone doses ranged between 20 mg/d to 85 mg/d; at 9 months the range was 10 mg/d to 90 mg/d. Serum concentrations of methadone and its metabolites were measured at day 1 and 2 during dose titration, and 1 week, 5 weeks, 3 months, and 9 months after the end of dose titration. Serum concentrations of methadone and its primary EDDP metabolite did not change significantly from the end of dose titration throughout the 9-month study period. Very low correlations between methadone dose and serum concentrations were observed, and there were large interindividual differences in serum concentrations and metabolism. Clinical Comment: The authors conclude that their findings contradict the notion that autoinduction of methadone metabolism takes place during long-term therapy and further suggest that a 3-day opioid switch from morphine to methadone followed by a 1-week titration period seems pharmacologically sound. Anecdotally, it has been previously reported that methadone dose increases typically are not necessary in patients receiving long-term therapy, unless there is a change in physical condition influencing the need for increased analgesia. However, this current study enrolled relatively few patients and several of them were taking either comedications potentially affecting methadone metabolism or supplemental codeine or morphine. Therefore, further research would be warranted to confirm the results.
References: Fredheim OM, Borchgrevink PC, Klepstad P, Kaasa S, Dale O. Long term methadone for chronic pain: A pilot study of pharmacokinetic aspects. Eur J Pain. 2006(Nov 17) [Epub ahead of print]. See: http://dx.doi.org/10.1016/j.ejpain.2006.09.006. Access checked 12/11/06. Tennant F. Tennant blood study: summary report – opioid blood levels in high dose, chronic pain patients. Practical Pain Management. 2006(March);6(2):28-41. < Back to Top > Migraine Assessment Tools Improve Patient CareSuccessful treatment of headaches requires an effective method of assessment and migraine headache can be especially difficult to diagnose and treat. A study, published in the December issue of the Journal of Family Practice, evaluated the diagnostic usefulness of 2 assessment tools that are part of the Migraine Care Program (see link below). The prospective study consisted of a 2 phases to evaluate: A) the usefulness of the Headache Assessment Quiz as an effective tool for migraine diagnosis, and B) the perceived usefulness of the Migraine Care Program for patients and primary care providers. In phase A, 49 healthcare clinicians administered the Headache Assessment Quiz and the Headache Impact Test (HIT-6) to patients. Of the total 1,527 patients who received screening results that were positive for migraine, 1,126 also received a confirming diagnosis from their primary healthcare provider; of these, 52% of patients stated that it was their first migraine diagnosis. In phase B, each clinician recruited up to 10 patients diagnosed with migraine in Phase A for 12 weeks of Migraine Care Program education and migraine care (total n=470). As a result of their participation in the program, more patients reported being ‘satisfied’ or ‘very satisfied’ with the medications used during the study than used before (41% vs 29%, respectively; p < 0.005). The overall patient satisfaction with the quality of care was higher during the study when compared with pre-study satisfaction (48% vs 32%; p < 0.001). Healthcare providers participating in the study indicated that use of the assessment tools had significantly reduced the difficulty of assessment. In addition, providers rated their perception of patient communication of headache severity and symptoms as improved with the use of the questionnaires (76% vs 20%; p < 0.001). The use of the HIT-6 improved the clinicians awareness of the importance of headache impact on treatment decisions. Clinical Comment: The Migraine Care Program is an educational service of GlaxoSmithKline for healthcare providers and patients (see, http://www.migrainecareprogram.com/ [access checked 12/11/06]). The investigators indicated that the motivation for this study was the high number of undiagnosed people with migraine headaches, the suboptimal quality of care, and the potential value of a better method to understand patients’ symptoms and resulting disability. – WD. Reference: Landy SH, Kwong WJ, Hutchinson S, et al. Migraine: a better way to recognize and treat it. J Fam Pract. 2006(Dec);55(12):1038-1047. < Back to Top > Massage Therapy Effective in Osteoarthritis of the KneeMassage therapy is an attractive treatment option for osteoarthritis (OA), but its clinical effectiveness is uncertain. Researchers conducted a randomized, controlled trial of massage therapy for radiographically confirmed OA of the knee in 68 adults. Subjects were assigned either to treatment (twice-weekly sessions of standard Swedish massage in weeks 1-4 and once-weekly sessions in weeks 5-8) or to control (delayed intervention). Primary outcomes were changes in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and functional scores, and the visual analog scale of pain assessment. The group receiving massage therapy demonstrated significant improvements (p < 0.001) in mean WOMAC global scores, and for pain, stiffness, and physical function domains. Significant improvements also were found in the visual analog scale of pain assessment, range of motion in degrees, and time to walk 50 ft. Findings were unchanged in multivariable models controlling for demographic factors. Practice Perspectives: The authors concluded that massage therapy in this study seemed to be efficacious in the treatment of OA of the knee. While this could be a worthwhile therapeutic modality to consider, it would be more helpful if comparisons and contrasts also were available with other approaches, such as medications, physical therapy, acupuncture (see next item below), and others. Further study of cost effectiveness and duration of treatment effects is clearly warranted for the various alternatives. – SBL. Reference: Perlman AI, Sabina A, Williams A-L, Njike VY, Katz DL. Massage therapy for osteoarthritis of the knee; a randomized controlled trial. rch Intern Med. 2006;166:2533-2538. < Back to Top > Acupuncture Reduces Knee and Hip Pain of OsteoarthritisOsteoarthritis (OA) of the hip and knee are chronic conditions that usually require continuous multi-disciplined care. Pain relief and the improvement or maintenance of functionality are the primary goals of management. In a controlled trial, patients were randomized either to 15 sessions of acupuncture during a 3-month period or to a control group that did not receive any acupuncture. All participants were allowed to participate in their usual medical care during the 6-month study period. In addition to the 632 total patients – 322 randomized to acupuncture and 310 to the control group – included in the study analysis, a total of 2,921 patients who requested acupuncture without randomization were allowed to participate in the study evaluation. Outcomes were measured using two assessment tools: 1) a health-related quality of life scale, and 2) the WOMAC scale (Western Ontario and McMaster Universities Osteoarthritis Index), which measures changes in pain, stiffness, and functionality. All patients had a mean baseline score of about 50. After the 3-month treatment period, the randomized acupuncture-group WOMAC mean scores were about 30 while the control group had mean scores of about 47. Scores of the nonrandomized acupuncture patients were similar to those of the randomized participants at 3 months. At 6-months, scores were slightly lower overall, but similar between randomized and nonrandomized acupuncture groups. Additionally, improvements in quality of life were reported as higher in the randomized acupuncture patients when compared with the control group. No differences were reported between the randomized acupuncture and control groups for medication prescriptions for OA during the 3 months following randomization. Approximately 5% of acupuncture patients reported bruising, minor bleeding, or pain at the needling sites, but there were no serious side effects. Practice Perspectives: The investigators acknowledge that the study has limitations, including: the broad inclusion criteria, wide variations in patients’ courses of treatment, and lack of blinding to treatment. However, they state that this study, one of the largest randomized trials of acupuncture, provides “further evidence that acupuncture is a safe intervention and the results are consistent with other large surveys.” In an editorial published in the same issue of Arthritis & Rheumatism (referenced below; p. 3375), Tao Liu and Chen Liu (both physicians at a Chinese teaching hospital), note that this study “demonstrates the potential value of this therapy in addition to routine care for OA of the knee and hip.” They add that the study “furthers our understanding of acupuncture and adds to the accumulated evidence supporting its efficacy.” – WD. Reference: Witt CM, Jena S, Brinkhaus B, et al. Acupuncture in patients with osteoarthritis of the knee or hip. A randomized, controlled trial with an additional nonrandomized arm. Arthritis & Rheumatism. 2006(Nov);54(11):3485-3493. < Back to Top > Duloxetine Reduces Diabetic Peripheral Neuropathy PainPain associated with diabetic peripheral neuropathy is common and can present as burning, stabbing, or tingling. Analgesic therapy can be challenging due to side effects of commonly used tricyclic antidepressants or anticonvulsants. A study published in Neurology evaluated the effectiveness and safety of duloxetine – Cymbalta®, a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) – in 334 patients with painful diabetic peripheral neuropathy without concomitant depression. Participants were randomly assigned to 12-week treatment groups taking either duloxetine 60 mg once daily (QD) or 60 mg twice daily (BID), or to a placebo group. Both treatment groups demonstrated a significant treatment effect; 43% of patients in the duloxetine 60 mg QD group and 53% in the BID-treated group achieved a 50% reduction in average pain response compared with only 27% of patients in the placebo-treated group. Treatment with duloxetine, at either frequency, demonstrated significantly rapid pain reduction and sustained response. Furthermore, all secondary measures of pain, except increased pain sensitivity, were significantly improved with the once- and twice-daily duloxetine regimen. Nausea was the most frequently reported side effect, but this usually decreased fairly soon after treatment initiation. Other side effects included dizziness, somnolence, and fatigue, but only resulted in a discontinuation rate of about 1%. Clinical Recommendation: The authors stated that 60 mg QD duloxetine represented the lowest consistently effective total daily dose in this study and a once-daily frequency provides advantages, so their recommendation in the management of diabetic peripheral neuropathy pain is 60 mg daily. They add that some patients may experience added benefits at doses up to 60 mg BID, but caution that higher doses may reduce tolerance. – WD. Source: Wernicke JF, Pritchett YL, D’Souza DN, et al. A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain. Neurology. 2006(Oct);67(8):1411-1420. < Back to Top > Pregabalin May Extend Pain Relief For Fibromyalgia SufferersAt the American College of Rheumatology annual meeting investigators presented results of a study of pregabalin [Lyrica®, an anticonvulsant approved for neuropathic pain] in patients with fibromyalgia pain. An initial drug-washout phase was followed by a 6-week open-label study enrolling 1,051 patients, 93% female, who had fibromyalgia syndrome for a median duration of just under 8 years. Participants were started at pregabalin 300, 450, or 600 mg/day, and further adjusted for optimal pain control and tolerability. At the end of the open-label phase, more than 60% of patients provided a self-report of pain reduction greater than 50% over baseline visual analog pain scores (VAS). In the next phase, a total of 566 participants were randomized to a 26-week double-blind phase of either the optimal individual pregabalin dosage established during the open-label phase or to placebo. The principal endpoint of this phase was the measurement of time until the loss of the therapeutic response. By day 7 of the double-blind phase, 25% of the patients taking the placebo had lost therapeutic response, whereas the same percentage of pregabalin subjects did not lose the analgesic benefit until the 34th day. At the end of the 26-week trial, nearly twice as many placebo participants (61%) as patients taking pregabalin (32%) had lost therapeutic response. Pregabalin side effects included mild to moderate symptoms of dizziness, somnolence, sinusitis, arthralgia, and anxiety. Clinical Implications: There is currently no FDA-approved treatment for fibromyalgia. While pain is the primary symptom for many patients, others report fatigue and sleep disturbances. Therefore, pregabalin may serve as a stand-alone treatment for some patients or, alternatively, as an adjunct therapy for patients who need medications for fatigue or sleep. – WD. Source: Crofford LJ, Simpson S, Young JP, Jr, et al. A six-month, double-blind, placebo-controlled, durability of effect study of pregabalin for pain associated with fibromyalgia. American College of Rheumatology Meeting, Nov. 11-15, 2006. Washington, DC. Abstract #L44. < Back to Top > Fish Oil for Chronic Neck and Back Pain ReliefChronic nonspecific neck and back pain is commonly treated with nonsteroidal anti-inflammatory drugs (NSAIDs), but this may incur a potential for associated complications. A retrospective survey published in Surgical Neurology evaluated the effectiveness of the omega-3 fatty acids (EPA and DHA) found in pharmaceutical grade fish oil supplements for pain relief. Patients (n=250) already taking NSAIDs to control chronic neck and back pain were selected from a neurosurgical practice and instructed to take 2400 mg/day of a fish oil supplement for 2 weeks, and 1200 mg/day thereafter. They also were asked to begin tapering their use of NSAIDs during weeks 3 and 4 of the study. A questionnaire requesting subjective information on pain reduction, side effects, and current NSAID use was sent to all participants at approximately one month after treatment initiation. Half of the participants returned the questionnaire and reported on their fish oil supplement use at an average of 75 days after supplement initiation. Of the 125 respondents, 60% stated that their joint pain had improved and 60% indicated a reduction in pain overall, while 59% reported the discontinuation of prescription NSAIDs. At the time of the survey, nearly 80% of respondents were taking 1,200 mg of the fish oil supplement and the remainder were still taking 2,400 mg/day. Eighty percent stated that they were satisfied with the results of the fish oil supplement and 88% stated that they would continue taking the supplement. There were only 2 reports of side-effects: loose bowel movements on 1,200 mg per day. Practice Perspectives: The investigators acknowledge several weaknesses in this retrospective study, including the lack of controls and long-term follow-up. They recommend that appropriately designed studies are needed to confirm their results, which demonstrated that nearly 60% of responding participants were able to discontinue their usage of NSAIDs. In an editorial published in the same issue of Surgical Neurology (referenced below; p. 325), J.I. Ausman, MD, PhD, states “the importance of this work to neurosurgeons is that now there is an analgesic agent that can take the place of the COX-2 inhibitors and be used with no side effects.” In fair balance, it should be noted that the FDA has previously cautioned that “consumers not exceed more than a total of 3 grams per day of EPA and DHA omega-3 fatty acids, with no more than 2 grams per day from a dietary supplement.” The maximum supplement amount used in this study (2,400 mg/d) exceeded that recommendation. – WD, SBL. References: FDA Announces Qualified Health Claims for Omega-3 Fatty Acids. FDA News. 2004(Sep 8). Available at: http://www.fda.gov/bbs/topics/news/2004/NEW01115.html. Access checked 12/11/06. Maroon JC, Bost JW. Omega-3 fatty acids (fish oil) as an anti-inflammatory: an alternative to nonsteroidal anti-inflammatory drugs for discogenic pain. Surgical Neurology. 2006;65(3):326-331. < Back to Top > BOTOX® May Help Relieve Pelvic-Floor Spasm PainThe pain and pressure of pelvic-floor spasm in women who do not respond to standard therapy can be challenging to practitioners. This double-blind, randomized, placebo-controlled study compared the effectiveness of botulinum toxin type A [BOTOX®] with placebo in reducing pain and pressure in women with chronic pelvic pain and spasm of more than 2 years duration. Injections of 80 units of botulinum toxin type A were administered to 30 women and a control group of 30 women received an injection of saline. Each participant in both groups received a total of 4 injections at 2 bilateral sites in the puborectalis and pubococcygeus muscles. Evaluation consisted of the measurement of pelvic-floor pressures by vaginal manometry and the assessment of 4 types of gynecological pain by visual analog scale (VAS) at baseline and at monthly intervals for 6 months. BOTOX treatment demonstrated significantly reduced nonmenstrual pain from baseline (VAS score 51 versus 22, p = 0.009). Both groups showed a significant reduction in dyspareunia (painful coitus) and resting pelvic-floor pressure; however, the reduction in the BOTOX participants was greater. A small improvement in quality of life was reported in the BOTOX group (some individual evaluation points were rated as statistically significant). While the placebo group had slightly more adverse effects than the BOTOX group, the treatment group had complications in 4 women, including stress incontinence in 2 of them. Clinical Implications: The investigators discussed the possible factors that could have contributed to the positive results in the placebo group, including reports of a decrease in muscle spasm due to the muscle needling associated with acupuncture in other studies. They recommended additional research to further define the use of BOTOX in women who are unresponsive to conservative treatment for the pain and pressure of pelvic-floor spasm. – WD. Reference: Abbott JA, Jarvis SK, Lyons SD, et al. Botulinum toxin type A for chronic pain and pelvic floor spasm in women. A randomized controlled trial. Obstetrics & Gynecology. 2006(Oct);108(4):915-923. < Back to Top > Lidocaine Patch Reduces Pain of Carpal Tunnel SyndromeMild-to-moderate carpal tunnel syndrome (CTS) is commonly treated by conservative measures in an attempt to reduce inflammation, relieve wrist pain, and alleviate numbness. This study compared the effectiveness and safety of the lidocaine patch 5% [Lidoderm®] with a regimen of naproxen 500 mg twice daily (BID) for the neuropathic pain of CTS. In a multicenter, parallel-group, open-label trial, 100 participants were randomized to receive 6-weeks of treatment consisting of 3 patches during every 24 hours (1 patch TID) or naproxen 500 mg BID. Several measurement tools were used to assess outcomes, which compared mean changes between baseline and week-6 pain as well as satisfaction scores. Both groups demonstrated significant reductions in Average Pain Intensity scores between baseline and week-6; but did not show a statistically significant difference between the two groups. Results of the Investigator Clinical Global Impression of Improvement assessment showed a significant difference favoring the lidocaine patch 5% compared with naproxen 500 mg BID. Patient satisfaction scores of “satisfied” to “very satisfied” were reported by almost 72% of the lidocaine patch users and by 63% of the naproxen 500 mg BID group; however, this difference was not considered statistically significant. There were no significant side effects in either group. Clinical Comment: This study demonstrated that the lidocaine patch 5% can provide a safe and effective option to treat mild-to-moderate CTS. Because CTS is frequently diagnosed in an aged population, it can be a useful alternative for patients who would benefit from a noninvasive, topical analgesic therapy, avoiding the potential risks of systemic NSAID medications. – WD. Source: Nalamachu S, Crockett RS, Gammaitoni AR et al. A comparison of the lidocaine patch 5% vs naproxen 500 mg twice daily for the relief of pain associated with carpal tunnel syndrome: a 6-week, randomized, parallel-group study. Medscape General Medicine. 2006;8(3):33. < Back to Top > Increased Pain Can Indicate Burn Injury Infection
Injury status was measured in 3 ways: 1) pain intensity was rated on a 100-mm visual analogue scale (VAS), 2) a burn severity index was used, and 3) the total burn surface was calculated on a burn surface chart as ‘minor,’ ‘moderate,’ or ‘major.’ Pain scores were recorded in the morning and afternoon daily. Results indicated that patients (n=60) who were diagnosed with wound infections generally had larger burn areas, higher severity scores, and longer hospital stays. Most infections occurred between 3 and 5 days after injury. Daily VAS results showed a clear increase in pain intensity when the wound infection started and showed greater pain intensity variation over time (see examples in Graph). The difference in morning VAS measures between patients with and without infection was rated as significant, whereas differences in afternoon assessments were not considered significant. Clinical Comment: The authors acknowledge that one limiting factor of the study was that daily pain measurements were not consistently performed by the same nurse, but added that the VAS tool used was the same instrument that had been in use for a minimum of 3 years by that nursing staff. They also stated that “results support the hypothesis that an increase in pain intensity is related to signs of wound infection.” In addition, they emphasize that nurses play an important role in the identification of a change in a patient’s condition, including pain intensity, and early management of wound infection can be important for a burn patient’s survival. – WD. Reference: Tengvall OM, Bjornhagen VC, Lindholm C, et al. Differences in pain patterns for infected and noninfected patients with burn injuries. Pain Management Nursing. 2006(Dec);7(4):176-182. < Back to Top > Recent Drug Approvals and AnnouncementsFollowing are briefs on new pain-management drug approvals as well as items related to safety concerns for existing products. If the FDA news website posted a specific announcement, the link to it has been provided below. All brand names are registered trademarks of their respective manufacturers. Additionally, the FDA Center for Drug Evaluation and Research website offers the option to search on any approved drug name or active ingredient at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm, and safety information is posted by FDA’s MedWatch at http://www.fda.gov/medwatch/safety/2006/safety06.htm. Methadone 5 mg and 10 mg Tablets – FDA Advisory on Adverse Events Serious Adverse Effects With Compounded Topical Anesthetic Creams Kadian® (Morphine Sulfate) Approved in New 80 mg Strength < Back to Top >
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Other research does appear to confirm that methadone blood concentration may not always relate directly to the dose, possibly due to individual variations of absorption and/or metabolism. In a small study of 32 patients receiving chronic oral methadone for pain, total daily doses ranged from 40 mg/d to 600 mg/d (mean 218, SD +/- 161), while blood levels ranged from 80 ng/mL to 2580 ng/mL (mean 495, SD +/- 555 at1-2 hours post-dosing). A moderate and significant overall correlation (r = 0.40, p = 0.018) was noted between dose and blood concentration, but this was influenced primarily by strong associations only at methadone doses less than or equal to about 200 mg/d (see Scatter Plot), and higher methadone doses do not necessarily produce correspondingly high serum concentrations (data from Tennant 2006). – SBL. 
Patients’ pain experiences in burn injuries are complex and infection is a common cause of death after a burn injury. In a study published in Pain Management Nursing, Swedish researchersexplored the hypothesis that increased pain is experienced if a burn wound becomes infected. Patients in the study (n=165) were infection-free more than 24 hours before study initiation and able to communicate fully with healthcare providers.