Introduction

Complex regional pain syndrome (CRPS), previously known as reflex sympathetic dystrophy, causalgia, or shoulder-hand syndrome, is a clinical entity characterized by classic neuropathic pain, autonomic involvement, motor symptoms, and trophic changes in the skin, nails, and hair. Various therapeutic modalities such as physical techniques, exercise therapy, procedures, medication, and spinal cord stimulators have been employed to control CRPS-related pain. Despite these treatment strategies, severe pain caused by CRPS often persists and progresses to the chronic phase. Based on the established pathology of CRPS, we constructed an algorithm for multimodal medication therapy in CRPS, including the medication dose and sequence of administration.

Algorithm for multimodal medication therapy

To manage pain caused by CRPS, the diagnosis should be confirmed in accordance with the Budapest criteria. Oral steroid pulse therapy is recommended for initial pain management in patients with CRPS (Fig. 1). Oral steroid therapy can reduce peripheral and central neuroinflammation, which contribute to the development of neuropathic pain during the acute and chronic phases [1]. Considering the dosage regimen, 1 mg/kg prednisolone acetate (maximum dose, 60–80 mg/day) should be prescribed as the initial dose, which is subsequently tapered to 10 mg every other day for 2 weeks [2]. If pain relief is achieved, a second cycle of prednisolone can be administered immediately, and a third cycle can be considered if the second cycle is more effective than the first. However, long-term prednisolone therapy is not recommended due to the well-known side effects of steroidal agents.

If steroid pulse therapy offers poor relief or is ineffective, treatment to control central sensitization in the chronic phase should be initiated. The basic mechanism of central sensitization involves glutamate secretion from the terminals of the spinal dorsal horn and primary sensory neurons and the response of N-methyl D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors to the secreted glutamate [3]. In addition, sustained release of glutamate can cause trafficking of AMPA receptor subunits in the dorsal horn of the spinal cord. Such changes contribute to hypersensitivity, which underlies persistent pain [4].

Accordingly, the therapeutic goal is to reduce glutamate secretion from the presynaptic membrane or decrease glutamate binding to AMPA and NMDA receptors in the postsynaptic membrane [5,6]. Blocking or inhibiting Ca²⁺, γ-aminobutyric acid (GABA), alpha-adrenergic, and Na⁺-mediated receptors can reduce glutamate secretion by primary sensory neurons. In addition, enhanced serotonin, dopamine, and norepinephrine secretion by synaptic interneurons can facilitate reduced glutamate secretion [3]. Gabapentinoids (pregabalin and gabapentin) are Ca²⁺ receptor ligands [7], whereas GABA receptor agonists include baclofen (GABA_B receptor), clonazepam (GABAA receptor), and diazepam (GABA_A receptor) [8]. Tizanidine and mirtazapine are alpha-2 adrenergic receptor agonists [9,10], while carbamazepine and lamotrigine are Na⁺ blockers [11]. In addition, selective serotonin reuptake inhibitors (fluoxetine and escitalopram), serotonin and norepinephrine reuptake inhibitors (venlafaxine and duloxetine), tricyclic antidepressants (amitriptyline), mirtazapine (enhanced secretion of serotonin and norepinephrine), and dopaminergic agonists (ropinirole and pramipexole) can increase serotonin, norepinephrine, and dopamine in the synapse [12-14]. Perampanel can be used to block AMPA receptors in the postsynaptic membrane of the spinal cord dorsal horn [5]. If intolerable pain persists despite taking these drugs, appropriate doses of μ-opioid receptor agonists, such as tramadol (or acetaminophen/tramadol) or narcotics (e.g., oxycodone and tapentadol), should be considered.

Instead of starting two or more medications concurrently, it is recommended to administer one medication for at least 2 to 3 days to determine efficacy. If the medication is effective, the dose is increased, and the next medication is added. If the medication is ineffective, it is stopped, and the next medication is started.

If pain persists despite all drug adjustments, ketamine (maximum dose of 0.35 mg/kg/hour; day 1, 50% of maximum ketamine dose with 500-mL normal saline [N/S] for 4 hours; day 2, 75% of maximum ketamine dose with 500-mL N/S for 4 hours; days 3–5, maximum ketamine dose with 500-mL N/S for 4 hours; days 6–7, no administration; days 8–13, maximum ketamine dose with 500-mL N/S for 4 hours) with midazolam 2 mg before and after ketamine injection can be administered intravenously to inhibit the NMDA receptor [15]. Given that patients may experience resistance to ketamine therapy, an interval of at least 3 months is recommended after treatment. If this treatment fails to afford sufficient efficacy, intravenous lidocaine can also be considered for 2 weeks (day 1, 1 mg/kg lidocaine with 500-mL N/S for 4 hours; day 2, 2 mg/kg lidocaine with 500-mL N/S for 4 hours; days 3–5, 5 mg/kg lidocaine with 500-mL N/S for 4 hours; days 6–7, no administration; days 8–13, 5-mg/kg lidocaine with 500-mL N/S for 4 hours) [16].

Conclusion

We hope that our proposed drug treatment algorithm to control CRPS pain will help clinicians appropriately treat patients with CRPS. However, as this proposed protocol has no supporting evidence, further studies targeting patients with CRPS are needed to evaluate its effectiveness. Moreover, since several studies on calcitonin, bisphosphonate, and botulinum toxin injection have been reported, we believe that the CRPS treatment algorithm should be continuously updated through many studies in the future [2,17,18].

Notes

Conflicts of interest

Min Cheol Chang has been Associate Editor of Journal of Yeungnam Medical Science since 2021. He was not involved in the review process of this manuscript. There are no other conflicts of interest to declare.

Funding

None.

Author contributions

Conceptualization: all authors; Writing-original draft: all authors: Writing-review & editing: all authors.

Fig. 1.

Algorithm of multimodal medication therapy in patients with complex regional pain syndrome. CRPS, complex regional pain syndrome; SNRI, serotonin-norepinephrine reuptake inhibitor; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; IV, intravenous; NMDA, N-methyl-D-aspartate.

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Figure & Data

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Citations

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