Ultrasound-guided Percutaneous Cryoneurolysis to Treat Chronic Postamputation Phantom Limb Pain: A Multicenter Randomized Controlled Trial

Abstract

Background: Postamputation phantom pain is notoriously persistent with few validated treatments. Cryoneurolysis involves the application of low temperatures to reversibly ablate peripheral nerves. The authors tested the hypothesis that a single cryoneurolysis treatment would decrease phantom pain 4 months later.

Methods: The authors enrolled patients with a lower-limb amputation and established phantom pain. Each received a single-injection femoral and sciatic nerve block with lidocaine and was subsequently randomized to receive either ultrasound-guided percutaneous cryoneurolysis or sham treatment at these same locations. The primary outcome was the change in average phantom pain intensity between baseline and 4 months as measured with a numeric rating scale (0 to 10), after which an optional crossover treatment was offered. Investigators, participants, and clinical staff were masked to treatment group assignment with the exception of the treating physician performing the cryoneurolysis, who had no subsequent participant interaction.

Results: Pretreatment phantom pain scores were similar in both groups, with a median [quartiles] of 5.0 [4.0, 6.0] for active treatment and 5.0 [4.0, 7.0] for sham. After 4 months, pain intensity decreased by 0.5 [-0.5, 3.0] in patients given cryoneurolysis (n = 71) versus 0 [0, 3] in patients given sham (n = 73), with an estimated difference (95% CI) of -0.1 (-1.0 to 0.7), P = 0.759. Following their statistical gatekeeping protocol, the authors did not make inferences or draw conclusions on secondary endpoints. One serious adverse event occurred after a protocol deviation in which a femoral nerve cryolesion was induced just below the inguinal ligament-instead of the sensory-only saphenous nerve-which resulted in quadriceps weakness, and possibly a fall and clavicle fracture.

Conclusions: Percutaneous cryoneurolysis did not decrease chronic lower extremity phantom limb pain 4 months after treatment. However, these results were based upon the authors' specific study protocol, and since the optimal cryoneurolysis treatment parameters such as freeze duration and anatomic treatment location remain unknown, further research is warranted.

Figure 1.

CONSORT diagram.

Figure 2.

Forest plot assessing interactions between prespecified baseline factors and the effect of ultrasound-guided percutaneous cryoneurolysis on phantom limb pain at 4 months. * P value was estimated from continuous pain score by multivariable linear regression adjusted for study site and day 0 average phantom limb pain.

Figure 3.

Effects of ultrasound-guided percutaneous cryoneurolysis (denoted in green) on the Brief Pain Inventory (BPI) interference domain over time. Data expressed as pain’s interference on each of 7 components (higher scores = more interference) demarked as median (dark horizontal bars) with 25th-75th (box), 10th-90th (whiskers), mean (diamonds), and outliers (circles). Following our statistical gatekeeping protocol, we do not make inference or draw conclusions on the secondary endpoints, since no difference was found on the primary endpoint.

Figure 4.

Effects of ultrasound-guided percutaneous cryoneurolysis (denoted in green) on worst, average, least and current phantom limb pain over time (primary outcome: average phantom limb pain at 4 months). Pain intensity indicated using a numeric rating scale of 0–10, with 0 equal to no pain and 10 being the worst imaginable pain. Data expressed as median (dark horizontal bars) with 25^th-75^th (box), 10^th-90^th (whiskers), mean (diamonds), and outliers (circles). Following our statistical gatekeeping protocol, we do not make inference or conclusions on the secondary endpoints, since no difference was found on the primary endpoint.

Figure 5.

Effects of ultrasound-guided percutaneous cryoneurolysis (denoted in green) on worst, average, least and current residual limb pain over time. Pain intensity indicated using a numeric rating scale of 0–10, with 0 equal to no pain and 10 being the worst imaginable pain. Data expressed as median (dark horizontal bars) with 25^th-75^th (box), 10^th-90^th (whiskers), mean (diamonds), and outliers (circles). Following our statistical gatekeeping protocol, we do not make inference or conclusions on the secondary endpoints, since no difference was found on the primary endpoint.