Chronic Pain

Annotated Abstracts of Journal Articles
2015, 3rd Quarter

Chronic Pain

Annotations by Elie Isenberg-Grzeda, MD and Sean Heffernan, MD
September 2015

  1. Clinical pain catastrophizing in women with migraine and obesity
  2. Combination of morphine with nortriptyline for neuropathic pain

PUBLICATION #1 — Chronic Pain
Clinical pain catastrophizing in women with migraine and obesity

Bond DS, Buse DC, Lipton RB, et al
Headache 2015; 55(7):923-933

ANNOTATION (Isenberg-Grzeda & Heffernan)

The Finding: One-quarter of the sample reported catastrophizing, which was also associated with more frequent attacks, longer attack duration, higher pain sensitivity, greater headache impact, and lower headache management self-efficacy.

Strength and Weaknesses: The biggest strength was the successful use of smartphone technology, which presumably improved participation and completion. The main weakness is the study design, which did not allow them to study causality between the variables measured.

Relevance: Pain catastrophizing encompasses a set of cognitions and affects that are aroused in response to actual or anticipated pain. It is a mediator of the experience of pain and is often associated with worse pain severity, disability, and quality of life. Pain catastrophizing has been studied in migraines and in obesity, but never in both, which is relevant because of the association between migraines and obesity. The findings in themselves are not revolutionary, but the study is an exciting one, particularly owing to its use of online smartphone technology to increase participation and completion rates.


Objective/Background: Obesity is related to migraine. Maladaptive pain coping strategies (eg, pain catastrophizing) may provide insight into this relationship. In women with migraine and obesity, we cross-sectionally assessed: (1) prevalence of clinical catastrophizing; (2) characteristics of those with and without clinical catastrophizing; and (3) associations of catastrophizing with headache features.

Methods: Obese women migraineurs seeking weight loss treatment (n = 105) recorded daily migraine activity for 1 month via smartphone and completed the Pain Catastrophizing Scale (PCS). Clinical catastrophizing was defined as total PCS score ≥30. The six-item Headache Impact Test (HIT-6), 12-item Allodynia Symptom Checklist (ASC-12), Headache Management Self-Efficacy Scale (HMSE), and assessments for depression (Centers for Epidemiologic Studies Depression Scale) and anxiety (seven-item Generalized Anxiety Disorder Scale) were also administered. Using PCS scores and body mass index (BMI) as predictors in linear regression, we modeled a series of headache features (ie, headache days, HIT-6, etc) as outcomes.

Results: One quarter (25.7%; 95% confidence interval [CI] = 17.2-34.1%) of participants met criteria for clinical catastrophizing: they had higher BMI (37.9 ± 7.5 vs 34.4 ± 5.7 kg/m2, P = .035); longer migraine attack duration (160.8 ± 145.0 vs 97.5 ± 75.2 hours/month, P = .038); higher HIT-6 scores (68.7 ± 4.6 vs 64.5 ± 3.9, P < .001); more allodynia (7.0 ± 4.1 vs 4.5 ± 3.5, P < .003), depression (25.4 ± 12.4 vs 13.3 ± 9.2, P < .001), and anxiety (11.0 ± 5.2 vs 5.6 ± 4.1, P < .001); and lower self-efficacy (80.1 ± 25.6 vs 104.7 ± 18.9, P < .001) compared with participants without clinical catastrophizing. The odds of chronic migraine were nearly fourfold greater in those with (n = 8/29.6%) vs without (n = 8/10.3%) clinical catastrophizing (odds ratio = 3.68; 95%CI = 1.22-11.10, P = .021). In all participants, higher PCS scores were related to more migraine days (β = 0.331, P = .001), longer attack duration (β = 0.390, P < .001), higher HIT-6 scores (β = 0.425, P < .001), and lower HMSE scores (β = −0.437, P < .001). Higher BMI, but not higher PCS scores, was related to more frequent attacks (β = −0.203, P = .044).

Conclusions: One quarter of participants with migraine and obesity reported clinical catastrophizing. These individuals had more frequent attacks/chronicity, longer attack duration, higher pain sensitivity, greater headache impact, and lower headache management self-efficacy. In all participants, PCS scores were related to several migraine characteristics, above and beyond the effects of obesity. Prospective studies are needed to determine sequence and mechanisms of relationships between catastrophizing, obesity, and migraine.

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PUBLICATION #2 — Chronic Pain
Combination of morphine with nortriptyline for neuropathic pain
Gilron I, Tu D, Holden RR, Jackson AC, DuMerton-Shore D
Pain 2015; 156(8):1440-1448

ANNOTATION (Isenberg-Grzeda & Heffernan)

The Finding: Treating neuropathic pain with combination therapy of TCAs and morphine significantly improves outcomes and only modestly adds to the side-effect profile.

Strength and Weaknesses: This is a well-designed 3-period crossover RCT in which all participants received all three interventions (nortriptyline alone, morphine alone, or both) in various sequences. These are hard studies to conduct and difficult to fund. The limitations include the small sample size and the fact that the time to titrate and washout medications between periods is substantial. Other strengths and limitations are discussed at length in the commentary on this article.

Relevance: Neuropathic pain is common and can be difficult to treat. While studies are emerging that look at the efficacy of combination therapies, little work has looked at combining TCAs and morphine, both of which have good efficacy as monotherapies. The authors’ findings will hopefully help providers at critical decision points in the treatment of neuropathic pain.


First-line neuropathic pain drugs, including tricyclic antidepressants, are not always effective, and opioids have been recommended as second line. This trial evaluates a nortriptyline-morphine combination, compared with each monotherapy. In this randomized, double-blind crossover trial, patients with neuropathic pain were enrolled at 1 site between January 25, 2010, and May 22, 2014, and randomized in a 1:1:1 ratio using a balanced Latin square design to receive oral nortriptyline, morphine, and their combination. During each of three 6-week periods, doses were titrated toward maximal tolerated dose (MTD). The primary outcome was average daily pain at MTD, and secondary outcomes included other pain, mood and quality of life measures, and adverse effects. Sixty-two patients were screened, 52 enrolled, and 39 completed at least 2 treatment periods. Average daily pain (0-10) at baseline was 5.3 and at MTD was 2.6 for combination vs 3.1 for nortriptyline (P = 0.046) and 3.4 for morphine (P = 0.002). Brief Pain Inventory scores for average and present pain were also significantly lower for combination vs each monotherapy. Combination treatment resulted in moderate-severe constipation in 43% vs 46% with morphine (P = 0.82) and 5% with nortriptyline (P < 0.0001). Combination treatment resulted in moderate-severe dry mouth in 58% vs 49% with nortriptyline (P = 0.84) and 13% with morphine (P < 0.0001). This trial suggests superior efficacy of a nortriptyline-morphine combination over either monotherapy with constipation, dry mouth, and somnolence as the most frequent adverse effects.


Editorial commentary:
Rowbotham MC: Tricyclic antidepressants and opioids—better together?
Pain 2015; 156(8):1373-1374

This piece provides a balanced commentary on the article by Gilron et al. It highlights the importance, strengths, and limitations of the study, and is a quick and concise read.

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