Successful Multimodal Treatment for Complex Regional Pain Syndrome in an Adolescent with Acute Lymphoblastic Leukemia: A Case Report

Abstract

Complex regional pain syndrome (CRPS) is a debilitating disorder that causes significant pain and can decrease the quality of life of affected individuals. This is the first report of CRPS in an adolescent oncology patient, whose symptoms successfully resolved with 3 weeks of intensive, multimodal, and multidisciplinary therapies. She experienced a complete return to pre-CRPS functional status within 10 weeks. The successful outcome of this case highlights the importance of early recognition of CRPS in the adolescent population and the need for a multimodal intensive treatment regimen to prevent the development of chronic pain and loss of limb function.

Introduction

Complex regional pain syndrome (CRPS) is a debilitating chronic pain syndrome characterized by sensory, vasomotor, sudomotor, and trophic changes as outlined in the International Association for the Study of Pain's (IASP's) Budapest Criteria for the Diagnosis of CRPS (Table 1).^1,2 CRPS is often localized to an extremity and follows an injury (e.g., fracture, sprain, and surgery), although an inciting event may not always be identified.^3,4 The distinction between CRPS types (Type I and Type II) is the presence of an identified nerve injury in Type II.⁵ Overall incidence is estimated at 26.2 per 100,000, with lower incidence in younger populations.^4,6

Table 1.

International Association for the Study of Pain Budapest Consensus Criteria for the Diagnosis of Complex Regional Pain Syndrome¹

(1) Continuous pain disproportionate to any inciting event (2) At least one reported symptom in at least three of the following categories: Sensory: hyperesthesia or allodynia Vasomotor: temperature asymmetry, skin color changes, or skin color asymmetry Sudomotor/edema: edema, sweating changes, or sweating asymmetry Motor/trophic: decreased range of motion, motor dysfunction (weakness, tremor, dystonia), or trophic changes (hair, nail, skin) (3) At least one sign at the time of evaluation in at least two of the following categories: Sensory: evidence of hyperesthesia (to pinprick) or allodynia (to light touch, deep somatic pressure, or joint movement) Vasomotor: evidence of temperature asymmetry (>1°C), skin color changes, or skin color asymmetry Sudomotor/edema: evidence of edema, sweating changes, or sweating asymmetry Motor/trophic: evidence of decreased range of motion, motor dysfunction (weakness, tremor, dystonia), or trophic changes (hair, nail, skin) (4) Absence of another diagnosis that better explains the signs and symptoms

The pathophysiology of CRPS is complex and multifactorial, including central and peripheral sensitization, central nervous system changes, sympathetic dysregulation, inflammation, immune-mediated effects, and psychological factors.⁷ Prompt diagnosis and treatment are crucial for symptom resolution; nevertheless, diagnosis is often delayed due to nonspecific signs and symptoms at presentation.^4,8

Most accepted pharmacological treatments are based on expert opinion and application of strategies effective in other chronic pain states, and aim to achieve sufficient analgesia to facilitate participation in physical therapy (PT), which is focused on desensitization and improving range of motion.^9,10 Therefore, a multidisciplinary approach integrating pharmacology, interventional strategies, psychology, occupational therapy (OT), and PT is necessary.

To our knowledge, this report is the first to describe a case of CRPS in an adolescent undergoing active cancer treatment. Our goal is to facilitate early recognition of CRPS, enabling prompt intensive multimodal treatment, concurrent with continuation of cancer-directed therapy.

Case Presentation

This 15-year-old female with T cell acute lymphoblastic leukemia (ALL), previously followed by our pain service for nociceptive pain related to steroid-induced avascular necrosis (AVN) of multiple joints and vincristine-related neuropathic pain of bilateral lower extremities, presented for right knee and ankle surgery for AVN. Her initial recovery was typical for this procedure, with complete resolution of postoperative pain. On postoperative day 11, she noted recurring pain, swelling, and discoloration of the right foot.

CRPS-I was diagnosed during postoperative week 6 based on the clinical signs and symptoms consistent with the Budapest Criteria (Table 1): allodynia (sensory), skin color asymmetry (vasomotor), edema (sudomotor), and shininess of the right lower extremity compared with the contralateral extremity (trophic) in the absence of another diagnosis that better explained the signs and symptoms.

Nerve conduction testing was not employed in the diagnostic work-up since the pain service clinicians felt that the elements of clinical diagnosis were sufficient. Upon establishing the diagnosis, a rigorous multimodal treatment plan included medications, PT, OT, and psychological interventions. Coordination of care between clinicians is often the driving force for successful outcomes in the management of complex CRPS cases; therefore, we outline hereunder the components of care coordinated across multiple disciplines.

Pharmacological Management

Before the CRPS diagnosis, a regimen of morphine, gabapentin, methadone, and lidocaine patches (Table 2) was directed to treat AVN-related nociceptive pain and vincristine-related neuropathic pain. Once diagnosed with CRPS, additional medications for neuropathic pain included amitriptyline and daily intravenous lidocaine infusions. Intravenous lidocaine infusions were administered a total of seven times for either 4 or 8 hours each, following our institutional guidelines for intravenous lidocaine infusions (Supplementary Appendix SA1), for 10 days.

Table 2.

Multimodal Treatment Modality Details

	Medication	Dosage and route	Frequency
I. Pharmacological management	Methadone Gabapentin or pregabalin Morphine Lidoderm patches Amitriptyline Mexiletine Lidocaine infusion	5 mg PO 600 mg PO 75 m PO 15–30 mg PO 5% lidocaine patch 25 mg PO 50–150 mg PO 1.5 or 2 mg/(kg·h)	2–3x daily 3x daily 2x daily Every 4 hours PRN Every 24 hours PRN At bedtime 2–3x daily Administered for 4 or 8 hours (for a period of 10 days)

	Week	Examples of therapies
II. Physical therapy	1	Graded motor imagery Mirror therapy to increase pain-free range of motion Nonweight-bearing restorative yoga postures for increased range of motion, stress relief, and relaxation
	2	Continued with all mentioned activities and added: Passive stretching of heel cords Neuromuscular re-education through weight shifting and single leg stance weight bearing on various tolerated surfaces Mimicking graded imagery flashcards of proposed motions for foot and ankle range of motion Weight-bearing yoga postures for range of motion and strengthening in functional planes NuStep for range of motion, strengthening, and cardiovascular endurance in modified weight-bearing state Pillowcase and towel toe scrunches for intrinsic strengthening and desensitization
	3	Continued with all mentioned activities and added: Weight-bearing heel cord stretching (quadruped, downward-facing dog, standing)
	4–7	Continued to increase resistance and weight-bearing activities, as tolerated Continued with the mentioned activities and added: Vinyasa yoga flow focusing on weight-bearing postures in various planes Increase weight-bearing and resistance of therapeutic strengthening and endurance exercises (i.e., NuStep, treadmill, yoga)

Desensitization therapy techniques implemented

III. Occupational therapy

1. Applying various smooth and rough materials, such as a tissue or dry wash cloth, to the dorsal and volar surfaces of the foot, proximally to distally 2. Submerging foot into various textured materials and various temperatures of materials (rice, water, textured socks, etc.) 3. Immersing foot in various textured materials while performing ankle range of motion (eversion/inversion, dorsiflexion/plantarflexion) 4. Searching with foot and toes in water/rice for various textured materials (marbles, cubes, etc.) and identifying objects (i.e., smooth, hard, edged, round) 5. Washing lower extremity with a wet washcloth for several minutes 6. Applying graded sensory stimulation to the lower extremity, including vibratory massage and deep pressure

	Week	Examples of interventions
IV. Psychological interventions	1	Sleep hygiene recommendations Behavioral coping skills (distraction) Cognitive strategies
	2	Psychoeducation (caregiver role in promoting patient's use of nonpharmacological pain management techniques) Clinical hypnosis
	3	Cognitive strategies Clinical hypnosis Mindfulness exercises Values-based intervention Goal setting (functional goals)
	4	Psychoeducation (reviewed relationship between physiological and psychological symptoms) Cognitive strategies Mindfulness exercises Goal setting (nutritional goals)
	5	Reinforcement of cognitive-behavioral coping skills Highlight progress toward functional goals
	6	Reinforcement of cognitive-behavioral coping skills Highlight progress toward functional goals Cognitive strategies Behavioral coping skills Mindfulness exercises
	7	Reinforcement of cognitive-behavioral coping skills Highlight progress toward functional goals Behavioral coping skills (activity pacing)

PO, per os; PRN, pro re nata.

During the lidocaine infusions, the patient experienced nearly complete resolution of pain and improvement in physical signs, facilitating concurrent PT sessions. This regimen was subsequently transitioned to an oral mexiletine regimen, based on a similar mechanism of action, which further contributed to improvement of pain and function.

Coordination of Care with Rehabilitation Services

PT was implemented three to four times weekly, with sessions of 30–60 minutes. Specific treatment modalities, including mirror therapy,¹¹ are outlined in Table 2, and goals for therapy are outlined in Table 3. Lidocaine infusions administered during PT sessions greatly facilitated comfortable participation in therapy. By week 3 of PT, the patient could participate with minimal pain, and the lidocaine infusions were discontinued.

Table 3.

Goals for Physical Therapy and Reported Pain Scores

Goals for PT for this patient
Functional goals:	(1) Patient will return to independence with functional mobility and gross motor skills.
Treatment goals:	(1) Patient will report ≤3/10 pain in right foot on three consecutive sessions. (2) Patient will adhere to home exercise regimen 6/7 days a week. (3) Patient will demonstrate bilateral single-leg stance ≥10 seconds on all surfaces (level ground, balance foam, and balance disk) without overt loss of balance or increase in pain in 3/5 trials. (4) Patient will demonstrate ≥4/5 bilateral lower extremity manual muscle testing of all major muscle groups. (5) Patient will demonstrate right lower extremity active range of motion ankle dorsiflexion ≥10°.

Patient-reported pain scores (0–10 scale)
Week after CRPS diagnosis	Range of pain scores reported during pain clinic visits	Range of pain scores reported during physical therapy
0 (before dx)	5–10	—
1	7–9	0–8
2	0–9	0
3	0–8	0–7
4	0–6	0
5	0–7	0
6	0	0
7	0	0
8	0	0

CRPS, complex regional pain syndrome; PT, physical therapy.

OT was implemented as one to two sessions weekly for 30–60 minutes. Desensitization therapy was utilized (Table 2), including techniques to restore the ability to independently perform activities of daily living. As the symptoms improved and functional goals were met, the frequency and duration of PT and OT sessions were gradually decreased.

At home, the patient was encouraged to follow a daily structured schedule of physical activities, including walking, bicycling, stair climbing, elliptical machine exercising, and swimming, and to practice the mirror therapy, desensitization exercises, and the psychological interventions outlined hereunder.

Coordination of Care with Psychology

Before CRPS diagnosis, the patient was followed by psychology for nonpharmacological management of chronic pain. She utilized several adaptive pain management strategies and reported finding distraction and engagement in day-to-day functioning (school, extracurricular activities, etc.) most helpful. After diagnosis of CRPS, these sessions' frequency increased to one to three times weekly, lasting 15–75 minutes, as individual, family, or caregiver-only sessions.

A cognitive-behavioral approach was implemented (Table 2), using nonpharmacological pain management techniques (distraction, activity pacing, etc.) and cognitive strategies (e.g., restructuring pain-related cognitions, coping statements, and positive self-statements). Clinical hypnosis, using individualized invitation and intensification with imagery of a place that the patient identified as being free from pain and anxiety, was integrated into therapy, with goals of decreasing pain and increasing relaxation.

CRPS Progression and Resolution

During the first week of treatment, the patient reported reduced pain scores of 0/10 during the lidocaine infusions, with pain slowly returning to preinfusion baseline levels soon after infusion completion. The lidocaine infusions concurrent with PT sessions helped reduce pain and facilitate active engagement. Based on the effectiveness of lidocaine infusions, oral mexiletine (similar mechanism of action) was started during week 2. During week 3, PT was completed without lidocaine infusions with pain reported as 0/10 all day for several days. Progress continued during weeks 4–5, and by weeks 6–8, she was successfully weaned off mexiletine, amitriptyline, and methadone, sequentially, without pain recurrence.

Twenty weeks after diagnosis of CRPS, the patient fell, leading to pain and swelling of the right ankle. A prophylactic lidocaine infusion was administered due to concerns for CRPS recurrence, but pain subsided without any CRPS signs or symptoms. The patient is >1-year post-CRPS diagnosis and continues to present complete resolution of CRPS while continuing treatment for ALL. We have included a supplemental reflection shared by the patient's family to portray their experience and to highlight the importance of early diagnosis and treatment of CRPS to prevent chronic devastating pain (Supplementary Data)

Discussion

Developing a pain rehabilitation program

In this case, the need for orthopedic surgery was generated by a complication of the cancer-directed therapy (corticosteroid-related AVN). This is further relevant to clinicians in the field of oncology, since after completion of orthopedic surgery, patients will return to the oncology care team to complete the cancer-directed therapy. In our case, after the diagnosis of CRPS, a referral to a specialized center for CRPS therapy was considered, as our institution does not have a formal intensive pain rehabilitation program. Given the patient's need for simultaneous management of CRPS and cancer-directed therapy, and the logistics of transferring her protocol-driven cancer treatment, we decided to design an intervention plan aimed to replicate the elements of therapy offered at a formal CRPS-specialized intensive pain rehabilitation center.¹²

Multifactorial etiology of CRPS

As often is the case with CRPS, the etiology and mechanisms of pain either remain poorly elucidated or are multifactorial. Despite the initial impression that the orthopedic surgery was the insult leading to CRPS in this case, the etiology may have been multifactorial. Pre-existing chronic pain may predispose to developing CRPS, and our patient had AVN-related pain of the right lower extremity. Before the surgical event, painDETECT questionnaire scores were consistently reported as 1, indicating a non-neuropathic pain.^13,14 Notably, this preoperative pain characterization drastically differed from the CRPS-related pain after surgery, which she described as “tingly and burning,” consistent with neuropathic pain.

Intraoperatively, the patient underwent right sciatic and femoral nerve blocks intended for postoperative analgesia, procedures that could have been inciting causes for CRPS. If CRPS was the result of a specific nerve injury, then the classification would change to CRPS-II. Given the timing of all events, it is difficult to determine a unique inciting cause of the CRPS in this patient, which is common. Regardless of CRPS type, the diagnosis and treatment course would have been the same.

Another potential contributing factor could be the chemotherapy, specifically vincristine, which can cause neuropathic pain and may induce the “first insult” in double crush syndrome, a theory that nerve damage at one site may render the distal nerve segment prone to injury and chronic pain.^15,16 The previous exposure to vincristine may have increased her risk of developing a chronic pain condition such as CRPS. We suspect that CRPS in patients with cancer may be underdiagnosed and under-reported, and that patients undergoing chemotherapy may have an increased risk for CRPS. To date, a single case of CRPS has been reported in an adult patient with cancer¹⁷; however, our study is the first to describe a case of CRPS in the adolescent oncology population.

Effectiveness of lidocaine and mexiletine

Gabapentin, amitriptyline, and methadone are common pharmacological treatments for chronic pain syndromes, including CRPS.^10,18,19 Although less frequently described, lidocaine and mexiletine act by inhibiting voltage-sensitive sodium channels, thus decreasing nerve signal transmission. In certain chronic pain syndromes, including CRPS, upregulation of peripheral sodium channels can lead to increased nerve signal transmission at lower thresholds and development of allodynia and hyperalgesia. Lidocaine and mexiletine are thought to affect these upregulated receptors, resulting in decreased signal transmission, allodynia, and hyperalgesia.²⁰

Although lidocaine is often used for pain management, mexiletine is an antiarrhythmic drug less commonly used for pain relief. Adverse effects of nausea, vomiting, dizziness, lightheadedness, and anxiety may be limitations of mexiletine use.²⁰ Despite these limitations, oral mexiletine may be a good choice at institutions that are unable to facilitate simultaneous lidocaine infusions and PT sessions. The mexiletine serum/plasma level correlated with this patient's high level of pain control was 0.3 μg/mL, slightly lower than the drug's reported therapeutic range of 0.5–2.0 μg/mL, which is based on serum predose (trough) draws at steady-state concentration. Our experience suggests that early implementation of lidocaine infusions and/or mexiletine may be effective for long-term resolution of CRPS symptoms.

Conclusion

We report the successful treatment of CRPS in an adolescent concurrently undergoing cancer treatment. To avoid disrupting the protocol-driven cancer-directed therapy, we implemented a CRPS treatment program, which included pharmacological modalities, psychological interventions, and intensive PT and OT focused on desensitization and preservation of function. Less common pharmacological modalities, including lidocaine infusions and mexiletine, facilitated participation in PT and OT and contributed to long-term resolution of symptoms.

Further studies are needed to analyze whether patients with cancer are at increased risk for multifactorial mechanisms for development of CRPS. Early recognition of CRPS and implementation of a multimodal treatment strategy are imperative for long-term symptom management and improved quality of life.

Author Disclosure Statement

All authors have significantly contributed to the article, have reviewed and agreed upon the article content, and there are no conflicts of interest to disclose.

Funding Information

H.M. was partially funded by grant #R25CA23944 from the National Cancer Institute, to support the Pediatric Oncology Education Program.

Supplementary Material

Supplementary Data

Supplementary Appendix SA1