Spinal cord stimulation and other modalities will benefit from greater understanding of gender discrepancies

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Beatrice Bretherton

Despite their clear significance in pain management, gender differences relating to the ways patients respond to neuromodulation therapies are relatively poorly understood and underpinned by a limited amount of definitive data. Beatrice Bretherton (Leeds, UK) discusses this existing evidence base and the importance of expanding it with future research across multiple fronts.

Based on current epidemiological research, pain is reported more frequently by women than men, and the prevalence of different pain conditions may differ between genders. For instance, neuropathic pain, defined by the International Association for the Study of Pain (IASP) as ‘pain caused by a lesion or disease of the somatosensory nervous system’,1 is thought to be more prevalent in women compared to men.2 Similarly, low back pain is higher in females than males, even when accounting for the increase in prevalence with advancing age.3 In contrast, migraine begins earlier in males than in females.2 It has a higher prevalence in boys than girls before puberty. Migraine then changes following puberty, whereby the incidence and prevalence increase more rapidly in girls than boys.

As well as evidence of these differences between men and women in the prevalence of pain conditions, it is thought that the frequency of pain reporting, the severity of pain and the degree of pain response to treatments that help with managing pain may also differ between genders.

In the UK, spinal cord stimulation (SCS) is a National Institute for Health Care and Excellence (NICE)-approved treatment for adults who have had chronic pain of neuropathic origin for more than six months with a visual analogue scale score >50mm despite conservative treatment. SCS is a neuromodulation therapy and comprises a surgically implanted battery (called an implantable pulse generator) which provides energy delivered by lead(s) placed in the epidural space to modulate the pain signalling in the spinal cord to relieve pain. Randomised controlled trials demonstrate in several neuropathic pain conditions that SCS is effective at reducing pain and improving health-related quality of life, pain-related disability, function and sleep whilst having a good safety profile.

Regarding differences between women and men in pain responses with SCS, there is currently only tentative evidence suggesting that gender may influence outcomes. For instance, in a 22-year experience review of SCS for treating several chronic benign pain conditions, more women (81.6%) experienced pain relief than men (76.6%) in the first year of treatment with SCS.4 However, males had higher success rates in the longer term than females with SCS. In a recently published study, women and men responded equally well to SCS despite ‘average pain’ being significantly lower in males than females before implantation of the therapy.5

Intriguingly, there may be differences between men and women in some of the safety aspects of neuromodulation therapies. For instance, with SCS, we found that a more significant percentage of males (5%) than females (1%) had their treatment revised during surgery due to fracturing of the leads that deliver the electrical stimulation. Additionally, more females (13%) than males (6%) had their SCS therapy entirely removed (explanted) due to insufficient pain relief. With further analysis, we found that the female gender and older age were more likely to have the SCS therapy entirely removed compared to the male gender and younger age. This increased likelihood of females having the SCS therapy removed has been reported by other research groups investigating SCS.6,7

It is essential to carefully consider potential gender differences when identifying and recommending treatment options, providing care and treatment, reviewing outcomes and optimising treatments. There is the potential for gender differences to contribute to care disparities between women and men, making neuromodulation treatments more complex. Therefore, awareness and education of possible gender differences are needed in multidisciplinary teams responsible for providing patient care.

Of course, this requires a systematic and reliable evidence base that healthcare guidelines and pathways can use to determine how best to consider gender differences when neuromodulation is a treatment option. Since the research investigating gender differences is discrepant and tentative, and raises ethical and clinical implications, there is a need for a body of research that explores gender differences in the following:

  • Prevalence of the chronic pain condition being investigated
  • Pretreatment pain severity
  • Pain treatment responses
  • Safety outcomes

This should include an evaluation of the factors that may modulate gender differences, including psychological, biological and social aspects. Furthermore, as there are many other forms of neuromodulation in addition to SCS (e.g. peripheral nerve stimulation and [transcutaneous] vagus nerve stimulation), gender differences with these therapies should be studied. Finally, to develop a holistic account of how neuromodulation may be influenced by differences between women and men, gender differences in other outcomes, such as sleep, quality of life, function, and so on, should also be investigated.

 

References:

  1. International Association for the Study of Pain. IASP Taxonomy. Neuropathic pain. 14 December 2017. Accessed 7 September 2021.
    https://www.iasp-pain.org/resources/terminology/#neuropathic-pain
  2. Fillingim R B, King C D, Ribeiro-Dasilva M C et al. Sex, gender, and pain: a review of recent clinical and experimental findings. J Pain. 2009; 10(5): 447–85. DOI: 10.1016/j.jpain.2008.12.001
  3. Wu A, March L, Zheng X et al. Global low back pain prevalence and years lived with disability from 1990 to 2017: estimates from the Global Burden of Disease Study 2017. Ann Transl Med. 2020; 8(6): 299. DOI: 10.21037/atm.2020.02.175
  4. Kumar K, Hunter G, Demeria D. Spinal cord stimulation in treatment of chronic benign pain: challenges in treatment planning and present status, a 22-year experience. Neurosurgery. 2006; 58(3): 481–96. DOI: 10.1227/01.NEU.0000192162.99567.96
  5. Bretherton B, de Ridder D, Crowther T et al. Men and women respond equally well to spinal cord and dorsal root ganglion stimulation. Neuromodulation. 2022; 25(7): 1015–23. DOI: 10.1111/ner.13484
  6. Van Buyten J-P, Wille F, Smet I et al. Therapy-related explants after spinal cord stimulation: results of an international retrospective chart review study. Neuromodulation. 2017; 20(7): 642–9. DOI: 10.1111/ner.12642
  7. Slyer J, Scott S, Sheldon B et al. Less pain relief, more depression, and female sex correlate with spinal cord stimulation explants. Neuromodulation. 2020; 23(5): 673–9. DOI: 10.1111/ner.13036

 

Beatrice Bretherton is a research fellow at Leeds Teaching Hospitals NHS Trust, and a visiting research fellow in the Faculty of Biological Sciences’ School of Biomedical Sciences at the University of Leeds, in Leeds, UK. Her research interests include the effects of non-invasive vagus nerve stimulation on autonomic function, mood and quality of life, as well as discrepancies within neuromodulation care and how different patient groups respond to brain stimulation therapies.


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