Sex-specific differences in the efficacy of traditional low frequency versus high frequency spinal cord stimulation for chronic pain

Abstract

IntroductionSpinal cord stimulation (SCS), an FDA-approved therapy for chronic pain, uses paresthesia (low frequency SCS (LF-SCS)) or paresthesia-free (such as high-frequency SCS (HF-SCS)) systems, providing analgesia through partially-elucidated mechanisms, with recent studies indicating a sexual dimorphism in pain pathogenesis (Bretherton et al., Neuromodulation, 2021; Paller et al., Pain Med 10:289–299, 2009; Slyer et al., Neuromodulation, 2019; Van Buyten et al., Neuromodulation 20:642–649, 2017; Mekhail et al., Pain Pract, 2021). We aim to evaluate SCS therapy sex effects based on paradigm, utilizing visual analog scores (VAS), perceived pain reduction (PPR), and opioid use.MethodsA retrospective cohort study of SCS patients implanted between 2004 and 2020 (n = 237) was conducted. Descriptive statistics and linear mixed methods analyses were used.ResultsHF-SCS (10 kHz) was implanted in 94 patients (40 females, 54 males), and LF-SCS in 143 (70 females, 73 males). At 3 months and 6 months, HF-SCS (p < 0.001) and LF-SCS (p < 0.005) had lower VAS scores compared to baseline (p < 0.005), with no differences across groups. PPR improved in both post-implantation (p < 0.006) and at 3 months (p < 0.004 respectively), compared to baseline persisting to 6 (p < 0.003) and 12 months (p < 0.01) for HF-SCS, with significantly better PPR for HF-SCS at 3 (p < 0.008) and 6 (p < 0.001) months compared to LF-SCS. There were no differences in opioid use from baseline for either modality; however LF-SCS patients used more opioids at every time point (p < 0.05) compared to HF-SCS.VAS was improved for all modalities in both sexes at 3 months (p = 0.001), which persisted to 6 months (p < 0.05) for HF-SCS males and females, and LF-SCS females. Female HF-SCS had improved PPR at 3 (p = 0.016) and 6 (p = 0.022) months compared to baseline, and at 6 (p = 0.004) months compared to LF-SCS. Male HF-SCS and LF-SCS had improved PPR post-implantation (p < 0.05) and at 3 months (p < 0.05), with HF-SCS having greater benefit at 3 (p < 0.05) and 6 (p < 0.05) months. LF-SCS males but not females used less opioids at 6 months (p = 0.017) compared to baseline; however this effect did not persist.On linear mixed model analyses, including age, sex and stimulator type, VAS decreased with age, at each timepoint, and had a trend towards increasing with female sex, while PPR increased at 3 and 6 months and lastly HF-SCS was associated with decreased opioid use.DiscussionPPR at 3 and 6 months improved to a greater extent in HF-SCS. HF-SCS females had improved PPR at 3 and 6 months, and only LF-SCS males used less opioids at 6 months, potentially indicating sex-based pathway. Future studies should further elucidate differences in sex-based pathways and identify optimal SCS opioid-sparing paradigms for chronic pain patients.

Variables associated with nonresponders to high‐frequency (10 kHz) spinal cord stimulation

“…In contrast, Slyer et al. reported that females were more likely to fail SCS therapy in the setting of concomitant depression, while Conic et al reported gender related outcomes differences in traditional versus high‐frequency SCS 54,55 . Odonkor et al 53 .…”

“…The most commonly studied variables are related to patient characteristics (age and gender), obesity/ BMI, diabetes, polysubstance use, psychological factors (depression, anxiety, and pain catastrophizing), history of spinal surgery, pain etiology (duration, type, and diagnosis), pre-operative disability levels, opioid use, and others. 36,41,43,45,[47][48][49][50][51][52][53][54][55][56]58,61,62 Despite increased awareness and research efforts to recognize these, the evidence T A B L E 5 Descriptive statistics on baseline opioid use in all subjects within the nonresponders and responders' group.…”

“…Several variables and factors have been suggested to identify patients who are less likely to benefit from SCS therapy. The most commonly studied variables are related to patient characteristics (age and gender), obesity/BMI, diabetes, polysubstance use, psychological factors (depression, anxiety, and pain catastrophizing), history of spinal surgery, pain etiology (duration, type, and diagnosis), pre‐operative disability levels, opioid use, and others 36,41,43,45,47–56,58,61,62 . Despite increased awareness and research efforts to recognize these, the evidence remains inconclusive with mixed results overall 37,44,60,61 .…”

“…In contrast, Slyer et al reported that females were more likely to fail SCS therapy in the setting of concomitant depression, while Conic et al reported gender related outcomes differences in traditional versus high-frequency SCS. 54,55 Odonkor et al 53 found that increasing age had significant effects on SCS success; however, this finding differs from Strauss et al and Bir et al suggesting that younger age predicted greater efficacy and male sex had a higher rate of SCS revision, respectively. 65,66 Overall, the evidence remains inconclusive, and it has been proposed that the potential gender differences seen in SCS outcomes might be attributed to variances in sex-specific pathways underlying pathophysiologic mechanisms of chronic pain, endogenous opioids, depression, and psychological disorders.…”

“…41,42 Despite enduring research efforts, it remains a challenge to predict SCS response and data results are mixed. 43,44 Several studies have reported an association of treatment failure with the presence of psychiatric illness, [45][46][47][48][49] pain catastrophizing behavior, 50 diabetes, obesity, and high body mass index (BMI), 36,51,52 age, 45,48,53 gender, 54,55 longer pain duration, 43 history of spinal surgery, 37,53 tobacco use, 56 and polysubstance abuse (alcohol, illicit drugs, and opioid use). 36,41,52,57,58 One of the main challenges in neuromodulation remains to predict which patients will benefit from SCS before implantation takes place.…”