Investigation of the use of gabapentinoid drugs in pain management

INTRODUCTION

Pain is one of the most common causes why individuals visit health-care facilities and seek medical care. Chronic pain is a debilitating condition that affects millions of people worldwide, causing physical disability and depression and significantly impairing their quality of life.^[1] The pharmacological approach to treating chronic pain requires the use of many agents such as acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), opioids, and anticonvulsants. Acetaminophen is generally ineffective for moderate-to-severe pain. NSAIDs have limited use in most patients with complex medical conditions. Opioids have the potential to cause addiction.^[1,2] To fill this gap in pain management, clinicians are increasingly prescribing gabapentinoids (gabapentin and pregabalin).^[1-3] It has been suggested that the increase in gabapentinoid prescribing may be due to the desire to avoid opioid analgesics. Although gabapentinoids were primarily developed as anticonvulsant drugs, their use for pain management has recently increased. Gabapentinoids contribute to the emergence of anticonvulsant, analgesic, and anxiolytic effects by reducing the release of glutamate, noradrenaline (norepinephrine), and substance P by binding to the α2-delta subunit of voltage-gated calcium channels. Gabapentinoids are mostly recommended for the treatment of neuropathic pain and fibromyalgia (FM) in adults, but they are also often used off-label for other pain disorders such as low back pain, sciatica, spinal stenosis, and migraine.^[2,4,5] The aim of this study was to investigate the kind of painful conditions in which gabapentinoids were used in the musculoskeletal and nervous systems and the preferred drug doses.

MATERIALS AND METHODS

RESULTS

The mean age of the patients was 59.54 ± 11.59 years and 82.1% were female and 17.9% were male. The indications for gabapentinoid utilization are presented in Figure 1. The diseases preferred for drug use were lumbar disc herniation (LDH) (39.3%), cervical disc herniation (CDH) (13.7%), spondylolisthesis (11.3%), diabetic peripheral neuropathy (DPN) (11%), frozen shoulder (39, 10.7%), gonarthrosis (10.4%), psoriatic arthritis (PsA) (8.5%), spondylosis (8%), FM (4.9%), carpal tunnel syndrome (4.7%), complex regional pain syndrome (CRPS) (four distal radius fracture, four humerus fracture, one distal tibia fracture, and one distal fibula fracture) (2.7%), restless leg syndrome (RLS) (1.1%), coxarthrosis (0.8%), postherpetic neuralgia (PHN) (0.8%), and hemiplegia (0.5%), respectively. There was significant female gender superiority in both pregabalin and gabapentin groups (P < 0.001). BMI was significantly greater in the pregabalin group (P = 0.027), whereas smoking was significantly higher in the gabapentin group (P = 0.004). Gabapentin was more preferred in the treatment of LDH, CDH, and DPN (P < 0.001, P = 0.020, and P < 0.001, respectively). Pregabalin was more preferred in the treatment of spondylolisthesis, frozen shoulder, gonarthrosis, FM, PsA, and CRPS (P < 0.001, P < 0.001, P = 0.002, P = 0.001, P = 0.001, and P = 0.026, respectively) [Table 1]. In whole chronic pain conditions, the VAS scores before and after 6 months of treatment were significantly reduced in both groups, except for RLS (P = 0.066) [Table 2 and Figure 2]. It was determined that the indication for gabapentinoid use was mainly related to neuropathic pain and gabapentinoid doses were below the recommended amounts [Table 3].

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Figure 1:

The indications for gabapentinoid utilization. LDH: Lumbar disc herniation; CDH: Cervical disc herniation; DPN: Diabetic peripheral neuropathy; PsA: Psoriatic arthritis; FM: Fibromyalgia; CTS: Carpal tunnel syndrome; CRPS: Complex regional pain syndrome; RLS: Restless le syndrome; PHN: Postherpetic neuralgia.

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Figure 2:

The median changes of Visual Analog Scale (VAS) scores before (VAS1) and after (VAS2) treatment for pregabalin and gabapentin. LDH: Lumbar disc herniation; CDH: Cervical disc herniation; DPN: Diabetic peripheral neuropathy; PsA: Psoriatic arthritis; FM: Fibromyalgia; CTS: Carpal tunnel syndrome; CRPS: Complex regional pain syndrome; RLS: Restless le syndrome; PHN: Postherpetic neuralgia

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DISCUSSION

Despite limited indications approved by the U.S. Food and Drug Administration (PHN for both gabapentin and pregabalin; DPN, spinal cord injury-associated neuropathic pain, and FM for pregabalin), gabapentin and pregabalin are widely prescribed off-label for a variety of other pain syndromes.^[2] Therefore, we evaluated the gabapentinoid utilization and doses in musculoskeletal and nervous system painful conditions. We found that the indication for gabapentinoid utilization was predominantly associated with neuropathic pain and gabapentinoid doses were below the recommended amounts.

A systematic review and meta-analysis found that gabapentinoids were ineffective in reducing pain or disability in low back pain or lumbar radicular pain compared to placebo.^[6] The Cochrane database systematic review found that: (a) gabapentin could provide good pain relief in PHN and DPN rather than other types of neuropathic pain compared with placebo,^[7] (b) pregabalin is effective in PHN, DPN, and mixed or unclassified post-traumatic neuropathic pain but not in human immunodeficiency virus neuropathy, and there was insufficient evidence for its effectiveness in central neuropathic pain,^[8] (c) there was insufficient evidence to support or refute the claim that gabapentin reduces pain in FM,^[9] (d) pregabalin produced a greater reduction in pain intensity in patients with FM.^[10] A systematic review found that gabapentinoids seem to be effective and safe for the management of osteoarthritis pain.^[11] A meta-analysis found that gabapentin and pregabalin were effective in treating RLS, with no difference between the treatments.^[12] A report by Goodman and Brett noted that the potential benefits of off-label gabapentinoid use are uncertain and that guidelines tend to overestimate gabapentinoid effectiveness.^[2] Although there is limited evidence to support off-label use of gabapentinoids for most painful clinical conditions, gabapentinoids may be significantly beneficial in a variety of chronic painful conditions. The results of our study also supported this position.

We could find no data regarding the use of gabapentinoids for pain management in PsA and frozen shoulder in previous data. A common comorbidity in PsA is FM, characterized by chronic widespread pain, fatigue, and poor functional status, with a reported prevalence ranging from 10% to 27%.^[13] Abnormal central pain responses due to underlying inflammation, just like neuropathic-like pain, play a role in the development of FM in patients with PsA.^[14] Frozen shoulder or adhesive capsulitis is a condition that causes progressive stiffness, pain, limited motion, and functional impairment in the shoulder due to excessive scar tissue or adhesions in the glenohumeral joint. It has been suggested that persistent nociception in the early stages of a frozen shoulder may lead to peripheral and later long-term central sensitization and increased activity of the sympathetic nervous system. Central sensitization, as in many other arthritic and rheumatic conditions, may compromise response to treatment.^[15] Therefore, we preferred gabapentinoids as a treatment option because the sensitization in the pain process contributed in both cases, thus, gabapentinoids may be an effective tool in the treatment of both conditions. However, further research is needed in this regard.

Külekçioğlu et al. investigated the gabapentinoid utilization rates in inpatients with musculoskeletal disorders and reviewed the conditions, doses, and durations of utilization. They identified gabapentinoid use in 27.9% of patients (14.2% gabapentin and 13.7% pregabalin). They determined that gabapentinoids were predominantly used for neuropathic pain indication and were used in lower than recommended doses.^[1] The results of our study were consistent with this study. Therefore, we think that treatment should be started at low doses and increased according to the response of the patient.

Pain can be categorized as nociceptive, inflammatory, or neuropathic. Both inflammatory and neuropathic pain are mediated by peripheral and central mechanisms. When inflammation and tissue or nerve damage occur, neuropeptides released from nociceptive neurons activate the immune system, causing the release of various cytokines, which contribute to peripheral sensitization by increasing sensory neuron excitability.^[16] Gabapentinoids have also been shown to have anti-inflammatory properties through their effects on cytokine levels extra their antinociceptive effects.^[17,18] Given the ability of gabapentinoids to modulate pain pathways and inflammatory processes, it is conceivable that these drugs could be used in the treatment of a wide variety of conditions, from neuropathic pain to chronic inflammatory diseases. Future studies are needed in this direction.

There was a female gender predominance in our study. Hormonal influences, genetic predispositions, and psychosocial stress factors may contribute to the higher frequency of chronic pain in women.^[19] Women are more prone than men to generalized hyperalgesia from recurrent visceral pain.^[20] This may explain why women are more likely to experience chronic pain than men.

The study has some limitations such as a small sample size, being a single-center and retrospective study, the lack of a control group, the absence of inpatients, the lack of quality of life measures, and the absence of long-term follow-up. However, this study provides useful information about the versatile uses of gabapentinoids in treating a range of painful conditions.

CONCLUSION

Originally developed as anticonvulsants, gabapentin, and pregabalin are increasingly used in the treatment of various types of pain, including neuropathic and musculoskeletal pain. Although gabapentinoids raise concerns about addiction, it should not be overlooked that gabapentinoids are useful in the treatment of chronic painful conditions when used in the correct indications and doses.