Behavioral cancer pain intervention dosing: results of a Sequential Multiple Assignment Randomized Trial : PAIN

Journal Logo

Research Paper

Behavioral cancer pain intervention dosing: results of a Sequential Multiple Assignment Randomized Trial

Somers, Tamara J.a,*; Winger, Joseph G.a; Fisher, Hannah M.a; Hyland, Kelly A.a; Davidian, Marieb; Laber, Eric B.c; Miller, Shannon N.a; Kelleher, Sarah A.a; Plumb Vilardaga, Jennifer C.a; Majestic, Catherinea; Shelby, Rebecca A.a; Reed, Shelby D.d,e; Kimmick, Gretchen G.f; Keefe, Francis J.a

Author Information
PAIN 164(9):p 1935-1941, September 2023. | DOI: 10.1097/j.pain.0000000000002915

Behavioral pain management interventions are efficacious for reducing pain in patients with cancer. However, optimal dosing of behavioral pain interventions for pain reduction is unknown, and this hinders routine clinical use. A Sequential Multiple Assignment Randomized Trial (SMART) was used to evaluate whether varying doses of Pain Coping Skills Training (PCST) and response-based dose adaptation can improve pain management in women with breast cancer. Participants (N = 327) had stage I-IIIC breast cancer and a worst pain score of >5/10. Pain severity (a priori primary outcome) was assessed before initial randomization (1:1 allocation) to PCST-Full (5 sessions) or PCST-Brief (1 session) and 5 to 8 weeks later. Responders (>30% pain reduction) were rerandomized to a maintenance dose or no dose and nonresponders (<30% pain reduction) to an increased or maintenance dose. Pain severity was assessed again 5 to 8 weeks later (assessment 3) and 6 months later (assessment 4). As hypothesized, PCST-Full resulted in greater mean percent pain reduction than PCST-Brief (M [SD] = −28.5% [39.6%] vs M [SD]= −14.8% [71.8%]; P = 0.041). At assessment 3 after second dosing, all intervention sequences evidenced pain reduction from assessment 1 with no differences between sequences. At assessment 4, all sequences evidenced pain reduction from assessment 1 with differences between sequences (P = 0.027). Participants initially receiving PCST-Full had greater pain reduction at assessment 4 (P = 0.056). Varying PCST doses led to pain reduction over time. Intervention sequences demonstrating the most durable decreases in pain reduction included PCST-Full. Pain Coping Skills Training with intervention adjustment based on response can produce sustainable pain reduction.

1. Introduction

Pain is common for patients with cancer. Moderate-to-severe pain is endorsed by nearly 40% of patients with cancer and affects patients' quality of life and health outcomes.15,37 Analgesics are an effective first-line treatment for cancer pain,34,36 yet undertreatment remains common, with one-third of patients reporting inadequate pain management.8 National guidelines recommend integrating psychosocial and pharmacologic interventions for optimal cancer pain management.27,34 Psychosocial interventions, such as behavioral pain management, are efficacious for reducing pain.29 However, optimal dosing of behavioral pain interventions is not known, and integration of these interventions remains low.

Pain Coping Skills Training (PCST) is a behavioral pain management intervention that has demonstrated efficacy in numerous clinical populations.1,2,5,10,26,31–33,38 Pain Coping Skills Training protocols teach patients cognitive–behavioral skills to enhance their pain self-management. Traditional randomized controlled trials of PCST have used a “one size fits all” approach with all participants receiving the same intervention, and outcomes are assessed postintervention. This approach is discordant with clinical practice, where intervention response is repeatedly assessed, and dose is adapted based on response.

This study used a Sequential Multiple Assignment Randomized Trial (SMART)19,24 design to evaluate whether varying doses of PCST and response-based dose adaptation can improve pain in women with breast cancer. The first aim assessed comparative evidence of pain severity response to differing initial doses expecting that participants randomized to PCST-Full would report a significantly greater reduction in pain severity compared with participants randomized to PCST-Brief. The second aim was to provide comparative evidence of pain response to entire dose sequences of PCST, which adjusted the second dose based on participant response to initial dose.

2. Methods

2.1. Study sample

A trial methods description has been published.12 Procedures were approved by Duke University (IRB No. Pro00070823) and complied with Health Insurance Portability and Accountability Act guidelines. Participants were recruited between November 2016 and October 2020 from the Duke Cancer Center (Durham, NC; N = 123), Duke Women's Cancer Care Raleigh (N = 199), and a clinic in the Duke Cancer Network (Henderson, NC; N = 5). Potentially eligible participants were identified by medical record review, provider referral, or self-referral. After the oncologist approval, research staff mailed a letter followed by a telephone call or clinic approach, completed screening, and obtained informed consent. Eligibility criteria included (1) stage I-IIIC breast cancer3 (initial or recurrence) within 2 years, (2) 18 years or older, (3) life expectancy >12 months, and (4) worst pain severity in past week >5 of 10 at screening.28 Exclusion criteria included (1) cognitive impairment,7 (2) severe psychiatric condition, and (3) PCST in the past 6 months.

2.2. Design

Figure 1 presents the 8 intervention sequences embedded and compared in the SMART design. After baseline assessment, participants were randomly assigned (1:1 allocation) to a five session PCST-Full or a one session PCST-Brief. Randomization was performed by an independent staff member. Participants were not blinded to condition, given that conditions had differing numbers of sessions. Study therapists were blinded to participants' assessment responses, and analyses were conducted by team members who did not interact with participants. Five to 8 weeks after randomization (assessment 2), pain severity was assessed. Those who responded to the initial intervention (ie, pain severity reduction >30%)16 were rerandomized to a maintenance dose (ie, PCST-Full Maintenance or PCST-Brief Maintenance) or no further intervention. Those who did not respond were rerandomized to an increased dose (ie, PCST-Plus or PCST-Full) or a maintenance dose (ie, PCST-Full Maintenance or PCST-Brief Maintenance). Assessment 3 was completed 5 to 8 weeks after rerandomization, and assessment 4 was completed 6 months after assessment 3. Sequential Multiple Assignment Randomized Trials are ideal for studying outcomes following entire intervention sequences that may adjust or modify an initial intervention based on response, where a sequence specifies a strategy for treating a patient over time.17,35 Supplemental Online Figure 1 (available at presents this process.

Figure 1.:
Eight intervention sequences embedded in the SMART design. PCST, Pain Coping Skills Training; SMART, Sequential Multiple Assignment Randomized Trial.

2.2.1. Initial randomization conditions

  • (1) Pain Coping Skills Training-Full (PCST-Full). Pain Coping Skills Training-Full consisted of five 60-minute weekly individual in-person sessions. Sessions focused on pain education22,23 and training in cognitive–behavioral pain management skills using behavioral rehearsal, modeling, guided practice, and feedback. Session one focused on training in progressive muscle relaxation and guided imagery.16,30 Subsequent sessions included training in activity–rest cycling, pleasant activity scheduling, applied relaxation, identifying and changing unhelpful pain-related thoughts, problem solving, and goal setting.9,14
  • (2) Pain Coping Skills Training-Brief (PCST-Brief). Pain Coping Skills Training-Brief consisted of one 60-minute individual in-person session. Session content was the same as the PCST-Full first session.

Participants in both initial conditions received 3 weekly caring text messages to prompt skills practice and provide encouragement.

2.2.2. Secondary/rerandomization conditions

  • (3) Pain Coping Skills Training-Plus after PCST-Full Nonresponse. Participants received 2 additional in-person sessions focused on skills practice emphasizing adherence followed by three weekly 20-minute telephone calls to review skills practice, problem solving, and assess progress.
  • (4) Pain Coping Skills Training-Full Maintenance after PCST-Full Nonresponse. Participants received 5 weekly 20-minute booster telephone calls to review skills practice, problem solving, and do a therapist-guided relaxation practice using techniques learned in the initial randomization condition.
  • (5) Pain Coping Skills Training-Full Maintenance after PCST-Full Response. Participants received the same secondary condition as described in #4.
  • (6) No Further Intervention after PCST-Full Response. Participants received no further intervention.
  • (7) Pain Coping Skills Training-Full after PCST-Brief Nonresponse. Participants received the condition described in #1.
  • (8) Pain Coping Skills Training-Brief Maintenance after PCST-Brief Nonresponse. Participants received 5 weekly 20-minute booster telephone calls to problem solving and practice therapist-guided PMR or imagery.
  • (9) Pain Coping Skills Training-Brief Maintenance after PCST-Brief Response. Participants received the same secondary condition as described in #8.
  • (10) No Further Intervention after PCST-Brief Response. Participants received no further intervention.

2.3. COVID-19 pandemic

After March 13, 2020, procedures were conducted through telephone because of the COVID-19 pandemic. Overall, 13.5% (44/327) of participants had at least one intervention session during the pandemic. There were no differences in response to PCST-Full or PCST-Brief based on delivery modality (χ2 = 0.03 and 0.23, respectively; P > 0.05).

2.4. Therapist training and treatment fidelity

Therapist training included a 2-day workshop and a 4-week certification process. Therapists were intervention certified after demonstrating >90% (M = 4.50/5.00) competence and adherence. The five study therapists (ie, PhD-level clinical psychologists and one advanced PhD clinical psychology student) received weekly supervision. Of 326 participants assigned to a therapist and 1804 total study sessions: Therapist 1 = 150 participants, 47% of sessions; Therapist 2 = 148 participants, 43% of sessions; Therapist 3 = 23 participants, 8% of sessions; Therapist 4 = 4 participants, 2% of sessions; and Therapist 5 = 1 participant, 0.2% of sessions. Intervention response differences between therapists were considered by comparing Therapist 1 and Therapist 2 as well as Therapist 1, Therapist 2, and the other 3 therapists combined. There were no significant differences in response at any time point by the therapist (P = 0.31-0.94).

Treatment fidelity was assessed by an independent PhD-level clinical psychologist. Twenty percent of session recordings (N = 108) were randomly reviewed. Competence and adherence were exceptional, with average ratings of 4.71 (SD = 0.28) and 4.75 (SD = 0.44), respectively.

2.5. Study measures

Participants completed standardized self-report measures online at assessments 1 to 4 receiving $30 for each assessment. Participant demographics and medical variables were collected at assessment 1.

2.5.1. Primary outcome

Pain severity was assessed with the Brief Pain Inventory (BPI)—Pain Severity subscale.4 Participants rated their pain over the past 7 days at its worst, least, and average as well as their current pain where 0 = no pain to 10 = worst pain imaginable (Cronbach α = 0.86). The primary outcome was percent change in pain severity from assessment 1 to assessment 2, calculated using the following formula: {([average of BPI severity items at assessment 2 − average of BPI severity items at Assessment 1]/average of BPI severity items at assessment 1) × 100}. Given this formula, negative values correspond to a pain reduction.

2.5.2. Initial intervention response

Response was categorized as follows: responders reported >30% reduction in their pain severity and nonresponders reported <30% reduction or a pain severity increase.

2.5.3. Intervention outcomes

Percent change in pain severity from assessment 1 to assessment 3 was calculated using {([average of BPI severity items at Assessment 3 − average of BPI severity items at Assessment 1]/average of BPI severity items at Assessment 1) × 100}. Similarly, percent change in pain severity from assessment 1 to assessment 4 was calculated using {([average of BPI severity items at Assessment 4 − average of BPI severity items at Assessment 1]/average of BPI severity items at Assessment 1) × 100}.

2.6. Sample size

An effective sample size of 284 was planned (N = 327 allowing for approximately 15% attrition) to provide 80% power to detect a 10% mean difference in the primary outcome of percent reduction in pain severity from assessment 1 to assessment 2 between PCST-Full and PCST-Brief assuming a standard deviation 30% in each group at a 0.05 two-sided level of significance.

2.7. Statistical analyses

To test the first aim, an average percent reduction in pain severity at assessment 2 between the 2 initial intervention conditions was compared (ie, PCST-Full vs PCST-Brief) using a standard 2-sided, 2-sample t test.

To test the second aim, the mean percent reduction in pain for each of the 8 intervention sequences embedded in the SMART at assessment 3 and assessment 4 was estimated and compared using specialized methods21,24,25 that take into account that the interventions received by a participant may be consistent with having followed more than one of the sequences. Specifically, a modification of the approach by Nahum-Shani et al.25 was applied using weights based on sample proportions randomized at each stage in place of known randomization probabilities (0.5 at each stage), which statistical theory leads to more precise estimators and more powerful tests.35 A χ2 statistic constructed from these estimates was the basis for a test of the null hypothesis of no difference in mean percent reduction in pain. Planned comparisons of pairs of sequences reflecting the least and most intensive approaches overall (sequences 1 and 8) and within each initial intervention (sequences 1 and 4 and sequences 5 and 8) were conducted using constructed Z statistics.

3. Results

3.1. Study participants and intervention adherence

Figure 2 presents randomization, response, and rerandomization details. Withdrawals were minimal (29/327; 8.9%) and consistent between initial randomization groups (χ2 = 0.03; P = 0.859). Table 1 presents participant (N = 327) characteristics. Pain Coping Skills Training-Full participants (n = 163) completed on average 4.33 (SD = 1.40) sessions with 77% completing all five sessions; 99% of PCST-Brief participants completed their session. In the second conditions, participants rerandomized to PCST-Full (n = 44) completed on average 3.75 (SD = 1.94) sessions with 64% completing all 5 sessions; participants rerandomized to PCST-Plus (n = 36) completed on average 1.53 (SD = 0.84) sessions with 75% completing both sessions. Across conditions with phone calls, 62% to 82% of participants completed all calls. Daily skills practice was assessed at assessments 2, 3, and 4 by asking participants how many times in the past 7 days they had used PCST skills (0 = not at all, 1 = one time, 2 = a few days, 3 = several days, 4 = almost every day, and 5 = every day). Across follow-up time points, participants reported using skills on average “several days” or “almost every day” in the past 7 days. Supplement Table 1, available at, presented reported means and standard deviation of skills practice at each assessment overall and by randomization condition.

Figure 2.:
Consort chart. PCST, Pain Coping Skills Training.
Table 1 - Participant demographic, medical characteristics, and pain at baseline.
Characteristic Overall (N = 327) PCST-Full (n = 163) PCST-Brief (n = 164)
Age, y, mean (SD) 57.19 (11.87) 56.93 (11.96) 57.45 (11.81)
 Caucasian 203 (62) 98 (60) 105 (64)
 Black or African American 97 (30) 52 (32) 45 (27)
 Other (eg, Asian) 22 (7) 11 (7) 11 (7)
 Declined 5 (2) 2 (1) 3 (2)
Not Hispanic or Latina 311 (95) 155 (95) 156 (95)
Married/living with partner 195 (60) 94 (58) 101 (62)
Bachelor's or graduate degree 173 (53) 81 (50) 92 (56)
Months since diagnosis, mean (SD) 10.11 (6.21) 9.85 (5.91) 10.37 (6.49)
Stage at diagnosis
 I 183 (56) 95 (58) 88 (54)
 II 113 (35) 52 (32) 61 (37)
 III 31 (9) 16 (10) 15 (9)
Surgical history*
 Single mastectomy 54 (17) 36 (22) 18 (11)
 Double mastectomy 65 (20) 28 (17) 37 (23)
 Breast conserving (eg, lumpectomy) 185 (57) 94 (58) 91 (56)
 Lymph node removal or dissection 286 (88) 145 (90) 141 (87)
 Breast reconstruction 73 (23) 39 (24) 34 (21)
Treatment in past week*
 Surgical procedure 22 (7) 10 (6) 12 (7)
 Chemotherapy 27 (8) 12 (7) 15 (9)
 Radiation 35 (11) 15 (9) 20 (12)
 Immunotherapy 31 (10) 15 (9) 16 (10)
 Endocrine therapy 49 (15) 25 (15) 24 (15)
 Clinical trial 4 (1) 3 (2) 1 (1)
Pain medication use*
 Over the counter 177 (54) 87 (53) 90 (55)
 Opioid 60 (18) 31 (19) 29 (18)
 Other medications used for pain 107 (33) 50 (31) 57 (35)
Pain severity (0-10), mean (SD)* 4.04 (1.73) 4.03 (1.81) 4.04 (1.65)
Data are presented as no. (%) or n of N (%) unless indicated otherwise.
*Total n between 323 and 326 for these data points.
Other self-reported medications for pain included corticosteroids, anticonvulsants, Lyrica, anxiolytics, antidepressants, anti-inflammatory, and muscle relaxants.
PCST, Pain Coping Skills Training; PCST-Full, five intervention sessions; PCST-Brief, one intervention session.

3.2. Aim 1

Aim 1 examined the average percent reduction in pain severity from assessment 1 to assessment 2 by initial randomization condition. Overall, there was a decrease in mean pain severity from assessment 1 to assessment 2 (Assessment 1 M [SD] = 4.0 [1.7]); Assessment 2 = 2.9 (1.8). As hypothesized, PCST-Full led to a greater mean percent reduction in pain than PCST-Brief (M [SD] = −28.5% [39.6%] vs M [SD] = −14.8% [71.8%], difference [SE] = −13.7% [6.7%], 95% confidence interval [CI] [−26.8% to −0.6%], P = 0.041). In examining the minimal clinically important difference (MCID; >30%) for pain severity, 51.0% of PCST-Full participants and 42.3% of PCST-Brief participants reported at least a 30% reduction in pain severity after their initial intervention assignment (P = 0.127).

3.3. Aim 2

Aim 2 compared the 8 intervention sequences embedded in the SMART study design (Fig. 1) by examining mean percent pain reduction from assessment 1 to assessment 3 and assessment 1 to assessment 4.21,24,25 Analyses included participants with available data at assessment 3 (n = 299) and assessment 4 (n = 291). The estimated mean percent reduction in pain by intervention sequence at assessment 3 and assessment 4 is presented in Table 2, along with the estimated mean percent reduction in pain at assessment 2 reported above (n = 307) after PCST-Full (the initial intervention for sequences 1-4) and PCST-Brief (the initial intervention for sequences 5-7).

Table 2 - Estimated mean percent reduction in pain by intervention sequence compared with assessment 1 at assessment 3 and assessment 4, with estimated mean percent reduction in pain compared with assessment 1 at assessment 2 for Pain Coping Skills Training-Full (initial intervention for sequences 1-4) and Pain Coping Skills Training-Brief (initial intervention for sequences 5-8).
Sequence Estimated mean (SE)
(95% CI)
Estimated mean (SE)
(95% CI)
Estimated mean (SE)
(95% CI)
S1 −30.0% (7.0%)
(−43.8% to −16.3%)
−38.5% (6.2%)
(−50.6% to −26.3%)
S2 −28.5% (3.2%)
(−34.7% to −22.3%)
−27.8% (6.8%)
(−41.1% to −14.5%)
−31.7% (6.1%)
(−43.7% to −19.8%)
S3 −39.2% (4.5%)
(−48.1% to −30.3%)
−41.8% (4.6%)
(−50.8% to −32.8%)
S4 −37.0% (4.2%)
(−45.2% to −28.7%)
−35.1% (4.5%)
(−43.8% to −26.3%)
S5 −33.85 (4.8%)
(−42.9% to −24.2%)
−37.1% (5.2%)
(−47.3% to −26.9%)
S6 −14.8% (5.8%)
(−26.3% to −3.4%)
−37.9% (4.2%)
(−46.2% to −29.6%)
−29.9% (5.5%)
(−40.7% to 19.0%)
S7 −20.1% (6.2%)
(−32.3% to −8.0%)
−20.8% (7.1%)
(−34.7% to −7.0%)
S8 −24.6% (5.9%)
(−36.0% to −13.1%)
−13.6% (7.2%)
(−27.7% to 0.6%)
95% CI, 95% confidence interval.

At assessment 3, the evidence of differences among sequences was inconclusive (P = 0.11). All sequences show an improvement in estimated mean percent reduction in pain over that achieved by the initial intervention in the sequence at assessment 2 (Table 2), suggesting that the effect of the initial intervention may be enhanced over time and by dose adjustment. At assessment 4, however, there was strong evidence that all sequences are not the same in mean percent pain reduction from assessment 1 (P = 0.027). Any sequence that started with PCST-Full exhibited at least a 30% estimated mean reduction in pain at assessment 4, while only 2 of the four sequences that started with PCST-Brief achieved this effect (Table 2). The least intensive, sequence 8, showed the smallest mean percent pain reduction at assessment 4.

Comparison of the most and least intensive sequences overall (sequences 1 and 8) did not demonstrate the evidence of a difference in mean percent reduction in pain from assessment 1 to assessment 3 (difference [SE] = −5.5% [9.1%], 95% CI [−23.5% to 12.4%], P = 0.55). Similarly, there was not sufficient evidence at assessment 3 of a difference between the most and least intensive sequences starting with PCST-Full (sequences 1 and 4; difference [SE] = 6.9% [8.1%], 95% CI [−8.9% to 22.7%], P = 0.39) nor between those starting with PCST-Brief (sequences 5 and 8) (difference [SE] = −9.0% [7.4%], 95% CI [−23.6% to 5.6%], P = 0.23). However, at assessment 4, evidence supporting differences was found between sequence 1 and sequence 8 (difference [SE] = −24.9% [9.5%], 95% CI [−43.5% to −6.3%], P = 0.009) and sequences 5 and 8 (difference [SE] = −23.6% [8.7%], 95% CI [−40.7% to −6.5%], P = 0.007), but not between sequences 1 and 4 (difference [SE] = −3.4% [7.5%], 95% CI [−18.1% to 11.3%], P = 65).

Supplemental Tables 2, 3, and 4 (available at present additional analyses providing insights into the evolution of mean percent pain reduction between assessments 3 and 4 for each sequence. Analyses suggest that sequences starting with PCST-Full might achieve durable, meaningful mean percent reduction in pain from assessment 3 to 4. Analyses comparing mean percent reduction in pain from assessment 1 to assessments 3 and 4 for PCST-Full vs PCST-Brief, marginalizing over subsequent interventions, also suggest sequences starting with PCST-Full may yield greater mean reduction in pain by assessment 4.

4. Discussion

Guidelines recommend routine integration of behavioral cancer pain interventions,34,36 yet little is known about optimizing these approaches. This trial rigorously examined behavioral pain intervention dosing in women with breast cancer and pain. As hypothesized, after initial randomization, PCST-Full participants reported significantly reduced pain severity compared with PCST-Brief participants (29% vs 15% reduction). Pain Coping Skills Training-Full led to an average pain reduction that approached being clinically meaningful6 (ie, >30% pain reduction), whereas PCST-Brief did not. Among PCST-Full participants, 51% reported a clinically meaningful pain severity reduction. Promisingly, and not statistically significantly different from PCST-Full, 42% of PCST-Brief participants also experienced a meaningful pain reduction.

Second doses of PCST that were adjusted based on response to the initial dose were examined. Based on the intervention sequence outcomes after the second intervention dose (approximately 4 months from baseline), participants demonstrated statistically significant average pain severity reduction from baseline. Response across sequences varied from 20% to 40%, with five of the 8 sequences resulting in clinically meaningful pain decreases (ie, >30%; Table 2). Although there were significant differences in mean percent reduction of pain severity between PCST-Full and PCST-Brief after the initial doses, there were no significant differences in pain severity at 4 months among sequences after the second dose. Thus, secondary PCST response-based dosing may be a strategy to improve pain severity outcomes.

At the 6-month follow-up, 6 of the 8 PCST intervention sequences demonstrated strong durability of response from immediately post-treatment. Specifically, 10 months after baseline, 7 of 8 intervention sequences continued to demonstrate statistically significant pain severity reductions (21%-42%), whereas one did not (14%), and 6 of 8 continued to demonstrate clinically meaningful pain severity reduction (ie, >30%). Pain reduction maintenance in response to a behavioral pain intervention at the long-term follow-up in a cancer population suggests that dose adjustment based on individual response or needs can lead to improved longitudinal outcomes. Many behavioral intervention trials have often had shorter follow-up periods and demonstrated a regression to the mean or baseline levels of symptoms.20,29

The intervention sequences that demonstrated durable pain reduction at the final time point included PCST-Full either as an initial dose or a secondary dose. The intervention sequences that demonstrated the least durability started with PCST-Brief, followed by PCST-Brief Maintenance or nothing (ie, sequences 7 and 8). The lowest dosing sequence showed a decrease in the maintenance of pain reduction from immediately postintervention to the final time point (25% to 14% reduction). Pain Coping Skills Training-Full included 8 different coping skills, while PCST-Brief included just 2 relaxation-focused skills. The full cadre of pain coping skills may be optimal for extended pain relief.

This study met a high accrual goal, had high adherence, and had high participant retention (91% completion) even within the context of a complicated trial design and the COVID-19 pandemic. This work also has areas for improvement. Of note, generalizability is limited as this study was conducted at a well-resourced single institution with well-trained staff and was delivered mostly in-person by experienced therapists. In addition, the focus on pain as an outcome limits our understanding of how decreases in pain may be related to other outcomes (eg, quality of life). Finally, PCST skills use in daily life is an important adherence variable and was not quantified but is important dosing data and likely could be collected through simple electronic data collection such as text messaging. These limitations can and should be addressed in future work (eg, effectiveness trial and broader assessment).

Multistage designs, such as SMARTs, are useful for testing and refining interventions to approximate actual clinical practice.24,25 Both initial PCST doses led to a clinically meaningful pain reduction in 51% (PCST-Full) and 42% (PCST-Brief) of participants; in 7 of 8 sequences, these reductions steadily improved or were maintained longitudinally. Pain Coping Skills Training is a nonpharmacological pain intervention, and varying PCST doses seem to lead to pain reduction. Pain Coping Skills Training protocols have the potential to be readily disseminated as they are manualized and brief and include relaxation and imagery (2 central skills) in audio form. Pain Coping Skills Training protocols can be efficaciously delivered either in-person or through telehealth,11 as well as delivered by several trained healthcare providers18 increasing accessibility particularly in areas with limited resources.13 Increasingly automating these protocols (eg, app, web-based, video) and enhancing the maintenance of the brief doses (eg, identify potent skills, practice reminders, motivational interviewing, and continued contact) could further intervention reach and decrease costs.

Conflict of interest statement

The authors have no conflicts of interest to declare.

Appendix A. Supplemental digital content

Supplemental digital content associated with this article can be found online at


This work was funded by an award from the National Institutes of Health (R01CA202779) to the first author (T.J. Somers).

Contributors: Conceptualization: T.J. Somers, F.J. Keefe, M. Davidian, S.D. Reed; Data curation: J.G. Winger, S.N. Miller; Formal Analysis: J.G. Winger, M. Davidian, E.B. Laber; Funding acquisition: T.J. Somers; Investigation: S.A. Kelleher, J.C. Plumb Vilardaga, C. Majestic; Methodology: T.J. Somers, M. Davidian, E.B. Laber; Project administration: S.N. Miller; Resources: S.N. Miller; Visualization: T.J. Somers, J.G. Winger; Writing—original draft: T.J. Somers, J.G. Winger, H.M. Fisher, K.A. Hyland; Writing—review and editing: T.J. Somers, J.G. Winger, H.M. Fisher, K.A. Hyland, M. Davidian, E.B. Laber, S.N. Miller, S.A. Kelleher, J.C. Plumb Vilardaga, C. Majestic, R.A. Shelby, Shelby D. Reed, G.G. Kimmick, F.J. Keefe.

Data availability: We will work with the Palliative Care Research Cooperative to deposit de-identified data in their de-identified quantitative data repository.


[1]. Bennell KL, Ahamed Y, Jull G, Bryant C, Hunt MA, Forbes AB, Kasza J, Akram M, Metcalf B, Harris A, Egerton T, Kenardy JA, Nicholas MK, Keefe FJ. Physical therapist-delivered pain coping skills training and exercise for knee osteoarthritis: randomized controlled trial. Arthritis Care Res 2016;68:590–602.
[2]. Bennell KL, Nelligan R, Dobson F, Rini C, Keefe F, Kasza J, French S, Bryant C, Dalwood A, Abbott JH, Hinman RS. Effectiveness of an internet-delivered exercise and pain-coping skills training intervention for persons with chronic knee pain: a randomized trial. Ann Intern Med 2017;166:453–62.
[3]. Breast Cancer Staging System. AJCC cancer staging manual. Springer, 2017.
[4]. Cleeland CS, Ryan KM. Pain assessment: global use of the brief pain inventory. Ann Acad Med Singap 1994;23:129–38.
[5]. Dorfman CS, Kelleher SA, Winger JG, Shelby RA, Thorn BE, Sutton LM, Keefe FJ, Gandhi V, Manohar P, Somers TJ. Development and pilot testing of an mHealth behavioral cancer pain protocol for medically underserved communities. J Psychosoc Oncol 2019;37:335–49.
[6]. Dworkin RH, Turk DC, Wyrwich KW, Beaton D, Cleeland CS, Farrar JT, Haythornthwaite JA, Jensen MP, Kerns RD, Ader DN, Brandenburg N, Burke LB, Cella D, Chandler J, Cowan P, Dimitrova R, Dionne R, Hertz S, Jadad AR, Katz NP, Kehlet H, Kramer LD, Manning DC, McCormick C, McDermott MP, McQuay HJ, Patel S, Porter L, Quessy S, Rappaport BA, Rauschkolb C, Revicki DA, Rothman M, Schmader KE, Stacey BR, Stauffer JW, von Stein T, White RE, Witter J, Zavisic S. Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J Pain 2008;9:105–21.
[7]. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–98.
[8]. Greco MT, Roberto A, Corli O, Deandrea S, Bandieri E, Cavuto S, Apolone G. Quality of cancer pain management: an update of a systematic review of undertreatment of patients with cancer. J Clin Oncol 2014;32:4149–54.
[9]. Keefe FJ, Abernethy AP, C Campbell L. Psychological approaches to understanding and treating disease-related pain. Annu Rev Psychol 2005;56:601–30.
[10]. Keefe FJ, Caldwell DS, Baucom D, Salley A, Robinson E, Timmons K, Beaupre P, Weisberg J, Helms M. Spouse-assisted coping skills training in the management of osteoarthritic knee pain. Arthritis Care Res 1996;9:279–91.
[11]. Kelleher SA, Winger JG, Dorfman CS, Ingle KK, Moskovich AA, Abernethy AP, Keefe FJ, Samsa GP, Kimmick GG, Somers TJ. A behavioral cancer pain intervention: a randomized noninferiority trial comparing in‐person with videoconference delivery. Psychooncology 2019;28:1671–8.
[12]. Kelleher SA, Dorfman CS, Plumb Vilardaga JC, Majestic C, Winger J, Gandhi V, Nunez C, Van Denburg A, Shelby RA, Reed SD, Murphy S, Davidian M, Laber EB, Kimmick GG, Westbrook KW, Abernethy AP, Somers TJ. Optimizing delivery of a behavioral pain intervention in cancer patients using a sequential multiple assignment randomized trial SMART. Contemp Clin Trials 2017;57:51–7.
[13]. Kelleher SA, Winger JG, Fisher HM, Miller SN, Reed SD, Thorn BE, Spring B, Samsa GP, Majestic CM, Shelby RA, Sutton LM, Keefe FJ, Somers TJ. Behavioral cancer pain intervention using videoconferencing and a mobile application for medically underserved patients: rationale, design, and methods of a prospective multisite randomized controlled trial. Contemp Clin Trials 2021;102:106287.
[14]. Kerns RD, Sellinger J, Goodin BR. Psychological treatment of chronic pain. Annu Rev Clin Psychol 2011;7:411–34.
[15]. Kroenke K, Theobald D, Wu J, Loza JK, Carpenter JS, Tu W. The association of depression and pain with health-related quality of life, disability, and health care use in cancer patients. J Pain Symptom Manage 2010;40:327–41.
[16]. Kwekkeboom KL, Wanta B, Bumpus M. Individual difference variables and the effects of progressive muscle relaxation and analgesic imagery interventions on cancer pain. J Pain Symptom Manage 2008;36:604–15.
[17]. Laber EB, Lizotte DJ, Qian M, Pelham WE, Murphy SA. Dynamic treatment regimes: technical challenges and applications. Electron J Stat 2014;8:1225–72.
[18]. Lamb SE, Hansen Z, Lall R, Castelnuovo E, Withers EJ, Nichols V, Potter R, Underwood MR. Group cognitive behavioural treatment for low-back pain in primary care: a randomised controlled trial and cost-effectiveness analysis. Lancet 2010;375:916–23.
[19]. Lei H, Nahum-Shani I, Lynch K, Oslin D, Murphy SA. A “SMART” design for building individualized treatment sequences. Annu Rev Clin Psychol 2012;8:21–48.
[20]. Linden A. Assessing regression to the mean effects in health care initiatives. BMC Med Res Methodol 2013;13:119.
[21]. Lunceford JK, Davidian M, Tsiatis AA. Estimation of survival distributions of treatment policies in two‐stage randomization designs in clinical trials. Biometrics 2002;58:48–57.
[22]. Melzack R. From the gate to the neuromatrix. PAIN 1999;82(suppl 1):S121–6.
[23]. Melzack R, Wall PD. Pain mechanisms: a new theory. Pain Forum 1996;5:3–11.
[24]. Murphy SA. An experimental design for the development of adaptive treatment strategies. Stat Med 2005;24:1455–81.
[25]. Nahum-Shani I, Qian M, Almirall D, Pelham WE, Gnagy B, Fabiano GA, Waxmonsky JG, Yu J, Murphy SA. Experimental design and primary data analysis methods for comparing adaptive interventions. Psychol Methods 2012;17:457–77.
[26]. Porter LS, Samsa G, Steel JL, Hanson LC, LeBlanc TW, Bull J, Fischer S, Keefe FJ. Caregiver-guided pain coping skills training for patients with advanced cancer: background, design, and challenges for the CaringPals study. Clin Trials 2019;16:263–72.
[27]. Scarborough BM, Smith CB. Optimal pain management for patients with cancer in the modern era. CA Cancer J Clin 2018;68:182–96.
[28]. Serlin RC, Mendoza TR, Nakamura Y, Edwards KR, Cleeland CS. When is cancer pain mild, moderate or severe? Grading pain severity by its interference with function. PAIN 1995;61:277–84.
[29]. Sheinfeld Gorin S, Krebs P, Badr H, Janke EA, Jim HS, Spring B, Mohr DC, Berendsen MA, Jacobsen PB. Meta-analysis of psychosocial interventions to reduce pain in patients with cancer. J Clin Oncol 2012;30:539–47.
[30]. Sloman R. Relaxation and the relief of cancer pain. Nurs Clin North Am 1995;30:697–709.
[31]. Somers TJ, Abernethy AP, Edmond SN, Kelleher SA, Wren AA, Samsa GP, Keefe FJ. A pilot study of a mobile health pain coping skills training protocol for patients with persistent cancer pain. J Pain Symptom Manage 2015;50:553–8.
[32]. Somers TJ, Kelleher SA, Dorfman CS, Shelby RA, Fisher HM, Rowe Nichols K, Sullivan KM, Chao NJ, Samsa GP, Abernethy AP, Keefe FJ. An mHealth pain coping skills training intervention for hematopoietic stem cell transplantation patients: development and pilot randomized controlled trial. JMIR Mhealth Uhealth 2018;6:e66.
[33]. Somers TJ, Kelleher SA, Westbrook KW, Kimmick GG, Shelby RA, Abernethy AP, Keefe FJ. A small randomized controlled pilot trial comparing mobile and traditional pain coping skills training protocols for cancer patients with pain. Pain Res Treat 2016;2016:1–8.
[34]. Swarm RA, Paice JA, Anghelescu DL, Are M, Bruce JY, Buga S, Chwistek M, Cleeland C, Craig D, Gafford E, Greenlee H, Hansen E, Kamal AH, Kamdar MM, LeGrand S, Mackey S, McDowell MR, Moryl N, Nabell LM, Nesbit S, O'Connor N, Rabow MW, Rickerson E, Shatsky R, Sindt J, Urba SG, Youngwerth JM, Hammond LJ, Gurski LA. Adult cancer pain, version 3.2019, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw 2019;17:977–1007.
[35]. Tsiatis AA, Davidian M, Holloway ST, Laber EB. Dynamic treatment regimes: statistical methods for precision medicine. Boca Raton, FL: Chapman and Hall/CRC, 2019.
[36]. UpToDate. Cancer pain management: general principles and risk management for patients receiving opioids. UpToDate, 2021. Available at: Accessed April 6, 2023.
[37]. van den Beuken-van Everdingen MH, de Rijke JM, Kessels AG, Schouten HC, van Kleef M, Patijn J. Prevalence of pain in patients with cancer: a systematic review of the past 40 years. Ann Oncol 2007;18:1437–9.
[38]. Winger JG, Ramos K, Kelleher SA, Somers TJ, Steinhauser KE, Porter LS, Kamal AH, Breitbart WS, Keefe FJ. Meaning-centered pain coping skills training: a pilot feasibility trial of a psychosocial pain management intervention for patients with advanced cancer. J Palliat Med 2022;25:60–9.

Behavioral pain intervention; Coping skills; SMART design; Breast cancer; Pain

Supplemental Digital Content

© 2023 International Association for the Study of Pain