December 2015
David Craig, PharmD | Editor


The Journal of Pain

Highlights from The Journal of Pain (Volume 16, No. 12, December 2015 Issue)

Journal of Pain cover

Pain and Health-Related Quality of Life After Pediatric Inpatient Surgery

Jennifer A. Rabbitts, Tonya M. Palermo, Chuan Zhou, and Rita Mangione-Smith; Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA; Seattle Children's Research Institute, Seattle, WA; Department of Pediatrics, University of Washington, Seattle, WA

Children who still have moderate to severe post-operative pain 1 month after a procedure often demonstrate impaired quality of life, according to research reported in The Journal of Pain.

In the United States, some 4 million surgical procedures are performed on children every year. Unfortunately, poorly controlled post-surgical pain is common and can govern stress responses after surgery and result in delayed recovery with significant post-surgical pain that may develop into chronic pain.

Researchers at Seattle Children’s Hospital collected data from the parents of 915 children admitted to the hospital for surgery from January 2012 to August 2013. They measured health-related quality of life (HRQOL) and pain in a large, heterogeneous, pediatric inpatient population from a presurgery baseline to 1-month follow-up at home. They also examined predictors of clinically significant changes in HRQOL in the children 1 month following surgery.

This is the first study to examine pain and HRQOL outcomes for short-term surgical recovery in a broad population of children undergoing a wide range of surgeries.

Study results showed that 23% of the children had a clinically significant deterioration in HRQOL from baseline to 1 month after surgery. Factors associated with HRQOL deterioration included higher child age and moderate to severe pain at 1-month follow-up. The findings confirmed the negative effects of ongoing pain on both physical and psychosocial health. Importantly, the researchers also noted that during the past several decades, little progress has been made in reducing children’s pain after inpatient surgery in the early postoperative period.

Finally, the study results indicate that short-term outcomes after surgery may have long-term implications for pediatric surgical patients, especially a heightened risk for pain problems months to years after surgery. 

Inhaled Cannabis for Chronic Neuropathic Pain: A Meta-Analysis of Individual Patient Data

Michael H. Andrea, George M. Carter, Naum Shaparin, Kathryn Suslov, Ronald J. Ellis, Mark A. Ware, Donald I. Abrams, Hannah Prasad, Barth Wilsey, Debbie Indyk, Matthew Johnson, and Henry S. Sacks; Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY; Foundation for Integrative AIDS Research, Brooklyn, NY

Icahn School of Medicine at Mount Sinai, New York, NY; Department of Neurosciences, University of California, San Diego, San Diego, CA; Department of Anesthesia and Family Medicine, McGill University, Montréal, Québec, Canada; AIDS Program, San Francisco General Hospital, University of California, San Francisco, CA; Department of Physical Medicine and Rehabilitation, VA Northern California and University of California Davis Medical Center, Sacramento, CA; Teachers College, Columbia University, New York, NY

Results of a meta-analysis from five randomized trials involving 178 participants published in The Journal of Pain suggests that inhaled cannabis may provide short-term relief for up to 20% of patients with neuropathic pain.

For the meta-analysis, a multicenter team of researchers compared the proportion of patients experiencing more than 30% clinical improvement in chronic neuropathic pain at baseline and after treatment with inhaled cannabis. They compared the reported primary outcome with the planned primary outcome in the study protocols to assess reporting bias.

The authors concluded the meta-analysis results show inhaled cannabis provides short-term neuropathic pain relief in 1 in 5 to 6 patients equally across chronic painful neuropathies of different causes. 



Highlights from PAIN (Volume 156, No. 12, December 2015 Issue)

Analgesic and Sedative Effects of Perioperative Gabapentin in Total Knee Arthroplasty: A randomized, Double-Blind, Placebo-Controlled Dose-Finding StudyPain Medicine Cover

Troels Haxholdt Lunn, Henrik Husted, Mogens Berg Laursen, Lars Tambour Hansen, Henrik Kehlet; Department of Anesthesiology, Copenhagen University Hospital, Hvidovre, Denmark; The Lundbeck Centre for Fast-Track Hip and Knee Arthroplasty, Copenhagen, Denmark; Department of Orthopedic Surgery, Copenhagen University Hospital, Hvidovre; Department of Orthopedic Surgery, Aalborg University Hospital, Farsø, Denmark; Department of Orthopedic Surgery, South of Denmark University Hospital, Grindsted, Denmark; Section of Surgical Pathophysiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen

Despite use of a multimodal pain management approach, acute postoperative pain intensity and opioid requirements are pronounced after total knee arthroplasty (TKA), and about 20% of the patients may develop persistent postsurgical pain. Conclusions from existing systematic reviews and meta-analyses are that gabapentin reduces acute postoperative pain, provides for opioid sparing, and potentially attenuates opioid-related side effects, but it may increase other side effects, mainly sedation and dizziness. The procedure-specific data for TKA are limited, and results are conflicting.

This study’s investigators studied the dose-related effect of gabapentin for 7 days initiated 2 hours preoperatively on acute postoperative pain in opioid-naive patients undergoing TKA. They conducted a large, randomized, double-blind, placebo-controlled dose-finding study. They aimed to investigate side effects and severe adverse reactions and hypothesized that gabapentin 1,300 mg/d would reduce pain upon ambulation 24 hours after surgery relative to placebo (primary outcome) but potentially increase sedation 6 hours after surgery (secondary outcome). They further hypothesized that gabapentin 1,300 mg/d would be superior to 900 mg/d.

Preoperative pain and other variables were similar in the 3 treatment groups, and perioperative data including hospital length of stay and adherence to protocol were similar. No statistically significant between-group difference was observed for pain upon ambulation 24 hours after surgery. Sedation 6 hours after surgery was increased in the gabapentin “high-dose” group vs. the placebo group.

These results could not confirm the hypothesis that gabapentin would reduce pain upon ambulation 24 hours after surgery, but the results confirmed the hypothesis that sedation 6 hours after surgery would be increased. In an exploratory analyses of other outcomes, no effects on overall pain during well-defined mobilizations and at rest from 4 to 48 hours or from days 2 to 6 and no opioid-sparing effects were observed with either gabapentin dose. The only benefit observed with gabapentin was an exploratory finding of improved sleep during the first to second postoperative night with both doses. Gabapentin may have a limited, if any, role in acute postoperative pain management for patients undergoing TKA, but should not be recommended as standard of care.

Predictive Factors for the Development of Persistent Pain After Breast Cancer Surgery

Kenneth Geving Andersen, Helle Molter Duriaud, Helle Elisabeth Jensen, Niels Kroman, Henrik Kehlet; Section for Surgical Pathophysiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Department of Breast Surgery, Rigshospitalet, University of Copenhagen, Copenhagen

Persistent pain after breast cancer surgery (PPBCS) is recognized as a major clinical problem affecting 25% to 60% of patients. The pain may last for years or be permanent after treatment. PPBCS negatively influences quality of life and causes reduced physical function. The pathophysiology of this pain is probably multifactorial and likely includes both patient- and treatment-related risk factors. The aim of this prospective study was to use a comprehensive validated questionnaire to prospectively examine a list of PPBCS risk factors in a well-described population of women with primary breast cancer who were studied from before surgery (baseline) to 1-year follow-up. To generate a basis for preventive and treatment strategies, the focus was on known patient and treatment characteristics that are present 2 to 3 weeks after surgery and the ways in which they helped to predict PPBCS 1 year later.

The prevalence of any pain after 1 year was 42%, and 14% of women had moderate to severe pain, which is slightly lower than prevalence observed in other studies, with about 50% to 60% reporting any pain and 15% to 25% reporting moderate to severe pain. These results suggest that young age is a risk factor for PPBCS, as is preoperative pain in the surgical area. Preoperative pain was measured after biopsies were taken, so the pain may be a consequence of undergoing a biopsy. Consistent with previous research on PPBCS and persistent pain occurrences after other types of surgery, acute postoperative pain in the area of surgery was a strong predictor. Neuropathic pain was a PPBCS predictor in the model of pain at rest but not for the model for pain during movement. Of the psychometric screening tools for anxiety, depression, distress, and pain catastrophizing, only the latter was not significantly associated with PPBCS in the univariate analysis. The association between psychological factors and PPBCS is well known, but investigators could not find this association in these data.

Of the treatment-related risk factors, axillary surgery was a significant predictor in both models, whereas sentinel lymph node biopsy significantly reduced risk for PPBCS. The combination of surgery and radiotherapy was a predictive factor for pain at rest. However, the larger radiation field of anterior thoracic wall radiotherapy and locoregional radiotherapy did not confer an increased risk, which provided the basis for an argument against radiotherapy as a risk factor. Mastectomy was a weak but significant predictor in the model for pain during movement but was nonsignificant after adjusting for lymphedema.

In conclusion, both patient- and treatment-related risk factors help to predict PPBCS. Younger patients with preoperative locoregional pain, a high intensity of acute postoperative pain, and signs of neuropathic pain during the acute postoperative phase indicate high risk. Identifying these patients may facilitate targeted interventions and reduce PPBCS. Risk factors may be used to inform patients and as a basis for identifying patients who need better psychosocial support and better control of postoperative and persistent pain.

Pain Medicine


Highlights from Pain Medicine (Volume 16, No. 11, November 2015 Issue)

High-Frequency Repetitive Transcranial Magnetic Stimulation Reduces Pain in Postherpetic Neuralgia

Shu-Min Ma, Jia-Xiang Ni, Xuan-Ying Li, Li-Qiang Yang, Yu-Na Guo, Yuan-Zhang Tang; Department of Pain Management, Xuanwu Hospital Capital Medical University, Beijing, 100053, China; Department of Anaesthesiology, University of Hong Kong-Shenzhen Hospital, Guangdong 518053, China

Postherpetic neuralgia (PHN), a painful complication associated with herpes zoster, is characterized by persistent pain that occurs between 1 and 6 months after healing of an associated skin rash. PHN is thought to be attributable to neural ischemia and intraneural capillary blood flow and, by 8 weeks, ischemic changes become irreversible, especially in the larger nerve fibers. The refractory chronic pain often disturbs activities of daily living and reduces quality of life. PHN is difficult to treat with conventional analgesics, and ineffective therapy has led to a high incidence of suicide in the elderly population.

The literature contends that noninvasive high-frequency repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) has pain-relieving effects in neuropathic pain (NP). The aim of this study was to assess the safety and efficacy of repeated daily administration of rTMS, targeting M1 in patients experiencing PHN.

The results of this randomized sham-stimulation controlled trial confirm that 10 daily sessions of M1 stimulation using rTMS may be effective in the setting of PHN to decrease pain intensity and reduce analgesic dosages without causing serious adverse events. The study also describes factors that may influence efficacy, such as duration of pain, patient age, pain location, and laterality.

The short-term efficacy of “real” rTMS subgroup patients who had experienced more than 6 months of disease was 32.27% (28.89%-51.92%). However, for patients who received “real” rTMS who had experienced fewer than 6 months of disease, the short-term efficacy was 51.92% (30.72%-73.12%).

In this study, analgesic effects appearing 2 days later lasted for 1 to 3 months after the stimulation. These data demonstrate that it is possible to maintain the analgesic effects of rTMS over a long period of time in patients with painful PHN. These results may be attributable to an additional effect from pharmacological treatment because pharmacological and rTMS treatment effects occur via different mechanisms.

This study demonstrates that daily high-frequency rTMS targeted over a painful region (face, hand, or foot) on M1 is tolerable and effective as an add-on to pharmacological treatment for patients with PHN.

The Relationship Between Sociodemographic Characteristics and Clinical Features in Burning Mouth Syndrome

Daniela Adamo, Antonio Celentano, Elvira Ruoppo, Claudia Cucciniello, Giuseppe Pecoraro, Massimo Aria, Michele D. Mignogna; Department of Neurosciences, Reproductive, and Odontostomatological Sciences and Department of Economics and Statistics, University Federico II of Naples

Burning Mouth Syndrome (BMS) is a complex chronic orofacial pain disorder characterized by an intraoral burning sensation for which no medical or dental cause can be found. The pain may be unremitting for at least 4 to 6 months. It is identified by three diagnostic criteria: pain in the mouth that is present daily and persisting constantly or for most of the day, oral mucosa of a normal appearance, and the absence of local and systemic diseases. BMS occurs more commonly in middle-age and elderly women and rarely affects individuals under the age of 30 years. Prevalence ranges between 0.7% and 3.6% in men and between 0.6% and 12.2% in women. The burning sensation in the oral mucosa and perioral regions usually has a bilateral and symmetric distribution. Sometimes the pain is described as scalding, tingling, or numbing. Other oral symptoms, such as dysgeusia, a bitter/metallic taste, subjective xerostomia, and foreign body sensation have been reported. The pain has precise physical, anatomical, and pathological dimensions, but is also characterized by cultural or universal components. This is because of the psychological, social, and cultural dimensions associated with nociception.

Although BMS has been extensively studied, little is known about the relationships between sociodemographic characteristics, symptoms, and triggers in the onset of disease. This study explored the sociodemographic profiles in a sample of patients with BMS; patients’ perceived pain intensity, the oral symptoms reported, the triggers in the onset of the disease, and the relationships with sociodemographic variables such as gender, age, educational level, marital status, and employment status; and the diagnostic delay comparing patient age with age at disease onset.

Gender and marital status did not influence age at disease onset. Conversely, educational level and job status were correlated with this factor; BMS is recognized earlier in patients who have a higher educational level and are employed. Investigators did not observe any statistically significant difference in pain intensity in relation to gender. Pain intensity in orofacial pain syndromes (such as temporomandibular disorders) will increase with the duration of the illness. This tendency was observed in the BMS patient sample; it is conceivable that the prolonged time for diagnosis (median 53 months) and the absence of treatment could contribute to increasing psychological stress of the patients and, consequently, pain intensity. Unemployed patients showed higher values on the Visual Analog Scale than employed patients. Unemployment could contribute to the psychological stress of patients and, consequently, could influence the pain intensity.

Taste disturbances were frequent in women and in unemployed people. The most frequent reported trigger reported was stressful life events, with antecedent dental procedures ranking third. However, antecedent dental procedures were the most common triggers among patients with the lowest educational level. Patients with the highest level of education could not identify a cause for their BMS. BMS remains an important medical condition that can place a significant burden on both patients and the healthcare system.