Experience from a single-center study on multimodal medication therapy for patients with complex regional pain syndrome

Abstract

BACKGROUND:

Despite the application of various therapeutic methods, pain caused by complex regional pain syndrome (CRPS) is not sufficiently managed and often progresses to a chronic stage. For the systematic and effective treatment of CRPS, we developed an algorithm for multimodal medication therapy based on the established pathophysiology of CRPS to control CRPS-related pain.

OBJECTIVE:

In this study, we present the outcomes of our novel algorithm for multimodal medication therapy for patients with CRPS, consisting of three major components: multimodal oral medication, intravenous ketamine, and intravenous lidocaine therapy.

METHODS:

We retrospectively investigated patients with CRPS who received multimodal therapy. Pain severity scores were evaluated using a numerical rating scale at four time points (P1, pain at initial consultation; P2, pain after oral medication; P3, pain after ketamine treatment; and P4, pain after lidocaine treatment). The effect of the multimodal medication therapy algorithm on pain management was evaluated at each time point.

RESULTS:

In patients with CRPS, multimodal oral medication, intravenous ketamine, and intravenous lidocaine therapies led to significantly improved pain control ( $p<$ 0.05). Additionally, the combination of these three therapies (through the multimodal medication therapy algorithm) resulted in significant pain relief in patients with CRPS ( $p<$ 0.05).

CONCLUSIONS:

Our multimodal medication therapy algorithm effectively controlled pain in patients with CRPS. However, further prospective studies with large sample sizes and randomized controlled trials are needed for more accurate generalization.

Keywords

Complex regional pain syndromes drug therapy neuralgia ketamine lidocaine

1. Introduction

Complex regional pain syndrome (CRPS) is a clinical entity characterized by classical neuropathic pain (allodynia, hyperalgesia, and burning pain); autonomic involvement (sweating, local edema, and altered skin color and temperature); motor symptoms (motor weakness and decreased range of motion); and trophic changes in the skin, nails, and hair [1]. Moreover, CRPS has been linked to several factors, including injuries, fractures, immobilization, and surgical interventions [2]. However, the exact pathophysiology of CRPS has not been elucidated. Patients with CRPS have been reported to experience severe disabling pain that typically affects the distal limbs and severely limits their day-to-day activities [2]. Various therapeutic methods, including exercise therapy, physical therapy, interventions, and medications, can be used to manage CRPS-related pain [3]. However, in many cases, despite the application of these therapeutic methods, pain from CRPS is not sufficiently controlled and progresses to a chronic stage.

Pain in the chronic stage of CRPS has been reported to result in neural plasticity or sensitization of the nervous system, including the peripheral nerves, spinal cord, and brain [2, 3, 4, 5, 6]. Therefore, pain in the chronic stage of CRPS is not a mere symptom of the disease but rather a disease of the nervous system [7]. Previous studies have suggested that a multimodal medication approach is necessary to manage chronic neuropathic pain [7]. However, few studies have evaluated the usefulness of multimodal medication approaches in chronic CRPS [8].

For the systematic and effective treatment of CRPS, we developed an algorithm for multimodal medication therapy based on the established pathophysiology of CRPS to control pain arising from the condition. In this current study, we present the outcomes of multimodal medication therapy for patients with CRPS.

2. Methods

2.1 Study design and population

This study was approved by the Institutional Review Board (IRB) of Ulsan University Hospital (IRB number: 22-04-037). Data from patients with CRPS treated at the Ulsan University Hospital between March 2020 and September 2022 were retrospectively collected. Clinical data such as age, sex, body weight, medications consumed, and numerical rating scale (NRS) pain scores (upon the first visit to our outpatient clinic, after oral medication, and after intravenous ketamine or lidocaine therapy) were obtained.

The inclusion criteria were as follows: (1) patients aged 20–89 years; (2) patients with CRPS diagnosed using the Budapest criteria; (3) patients in the chronic stage of CRPS ( $>$ 6 months after onset); and (4) patients who visited our outpatient clinic and underwent multimodal medication therapy. The exclusion criteria were as follows: (1) patients with impaired cognition (Mini-Mental Status Examination score $<$ 18) and (2) those with psychological disorders, including schizophrenia and bipolar disorder. This study was performed following the Declaration of Helsinki for human experiments, and the requirement for informed consent was waived owing to the retrospective nature of the study.

Figure 1.

The algorithm of multimodal medication therapy.

2.2 Multimodal medication therapy protocol

The algorithm used for multimodal medication therapy in patients with CRPS is displayed in Fig. 1. This algorithm comprised four steps: administration of oral steroid pulse treatment, multimodal oral medication therapy, intravenous ketamine therapy, and intravenous lidocaine therapy.

As an initial step in multimodal medication therapy, oral steroid pulse treatment was administered [9]. This treatment aims to reduce both peripheral and central neuroinflammation. The oral steroid pulse treatment was performed as follows: 60 mg of prednisolone acetate was prescribed for 3 days, which was subsequently tapered to 10 mg daily for 9 days [9]. If the patient’s pain was relieved after the first cycle of prednisolone, a second cycle of prednisolone was administered immediately, and a third cycle was considered if the second cycle was more effective than the first cycle. However, long-term prednisolone therapy is not recommended due to the well-known side effects of steroidal agents. Additionally, if steroid pulse therapy offered poor relief or if the pain persisted despite treatment, we no longer considered inflammation as the main cause of persistent pain in patients with CRPS, prompting us to proceed to the next step, which involved controlling central sensitization in the chronic phase.

Oral medications aimed at controlling central sensitization were administered as follows. To reduce glutamate secretion on the presynaptic membranes of primary sensory neurons, gabapentinoids ( $\alpha$ 2 $\delta$ -1 Ca²⁺ receptor ligands) such as pregabalin or gabapentin [10], baclofen (a gamma-aminobutyric acid_B [GABA_B] receptor agonist) [11], clonazepam (a GABA_A receptor agonist) [11], diazepam (a GABA_A receptor agonist) [11], tizanidine (an alpha-2 adrenergic receptor agonist) [12], clonidine (an alpha-2 adrenergic receptor agonist) [12], carbamazepine (a Na⁺ receptor agonist) [13], lamotrigine (a Na⁺ receptor agonist) [13], venlafaxine (a serotonin and norepinephrine reuptake inhibitor; SNRI), duloxetine (an SNRI) [14], tricyclic antidepressant (TCA) amitriptyline (a serotonin and norepinephrine transporter blocker) [14], and mirtazapine (a medication that enhances the release of both serotonin and norepinephrine) [15] were used. To reduce pain transmission at the post-synaptic membrane, perampanel (an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA] receptor blocker) was prescribed [16]. If the pain persisted despite the aforementioned medications, we considered the use of tramadol, acetaminophen/tramadol, or narcotics (oxycodone or tapentadol) at appropriate doses as $\mu$ -opioid receptor agonists [17].

Figure 2.

Pain assessment at various time points in accordance with the multimodal medication therapy used.

When prescribing oral medications, our approach was to initiate one medication at a time and continue the medication for at least 2–3 days to assess the effectiveness. If the medication proved effective (resulting in a reduction of more than 30% on the NRS), the dose was increased, and the next medication was added. If the medication proved ineffective, it was discontinued, and the administration of the next medication was initiated. On average, the interval from commencing the oral agent to commencing intravenous treatment was 29.07 $\pm$ 13.55 days.

If pain persisted despite all the therapeutic agents mentioned (NRS $\geqslant$ 5), intravenous ketamine or lidocaine therapy was prescribed [18, 19]. In all patients with CRPS in this study, intravenous ketamine treatment was initially administered, and lidocaine treatment was only considered if intravenous ketamine treatment yielded no or unsatisfactory effects. Ketamine treatment was performed according to the following protocol: day 1, 50% of the maximum dose of ketamine (maximum dose $=$ 0.35 mg/kg/hour) with 500 mL of normal saline (N/S) for 4 hours; day 2, 75% of the maximum dose of ketamine with 500 mL of N/S for 4 hours; days 3–5, 100% of the maximum dose of ketamine with 500 mL of N/S for 4 hours, followed by days 6–7 as rest periods; days 8–13, 100% of the maximum dose of ketamine with 500 mL of N/S for 4 hours. In cases of unrelenting and persistent pain, intravenous midazolam (2 mg) was administered before and after the ketamine injections to inhibit N-methyl-D-aspartate (NMDA) receptors. Given that patients may experience resistance to ketamine therapy, an interval of at least 3 months was recommended after treatment. Finally, if the treatment failed to provide sufficient efficacy, intravenous lidocaine with 500 mL of N/S (day 1, 1 mg/kg of lidocaine with 500 mL of N/S for 4 h; day 2, 2 mg/kg of lidocaine with 500 mL of N/S for 4 h; days 3–5, 5 mg/kg of lidocaine with 500 mL of N/S for 4 h; days 6–7, rest period; and days 8–13, 5 mg/kg of lidocaine with 500 mL of N/S for 4 h) was considered for 2 weeks.

2.3 Patient classification

In this study, all chronic stages of CRPS were categorized into two groups: the ketamine group, which did not progress to intravenous lidocaine therapy due to a sufficient response to intravenous ketamine therapy, and the lidocaine group, which received intravenous lidocaine therapy owing to pain that could not be controlled through intravenous ketamine therapy.

2.4 Pain measurement

The NRS was used as a pain measurement tool. Furthermore, the NRS pain scores were measured at four time points: at the initial consultation (P1), after administering the oral medication treatment (P2), after administering the intravenous ketamine (P3), and after administering the intravenous lidocaine treatment (P4) (Fig. 2). Patients were asked to indicate the highest level of pain they experienced during these periods.

2.5 Statistical analysis

To evaluate the effects of each step of the multimodal medication therapy, differences among NRS scores at each time point were analyzed using a paired $t$ -test or Wilcoxon signed-rank test in accordance with the non-parametric test results acquired using the Kolmogorov–Smirnov test. We also compared the effects of each step of the multimodal medication therapy separately in the ketamine and lidocaine groups. Statistical significance was set at $p<$ 0.05. Statistical analyses were performed using MedCalc (MedCalc Software Ltd., Ostend, Belgium) and SPSS (version 22.0; IBM Corp., Armonk, NY, USA).

Table 1
Characteristics of the patients with CRPS

Group	Ketamine group	Lidocaine group	Total
Number	39	6	45
Age (years)	51.62 $\pm$ 11.09	54.33 $\pm$ 5.72	51.98 $\pm$ 10.53
Sex (male: female)	21:18	4:2	25:20
Body weight (kg)	68.56 $\pm$ 12.04	63.17 $\pm$ 3.04	67.84 $\pm$ 11.72
NRS at the initial consultation (P1)	9.83 $\pm$ 0.33	9.83 $\pm$ 0.41	9.83 $\pm$ 0.34
NRS after oral medication administration (P2)	8.26 $\pm$ 1.49	8.75 $\pm$ 1.08	8.32 $\pm$ 1.44
NRS after ketamine administration (P3)	5.20 $\pm$ 1.30	8.42 $\pm$ 1.28	5.68 $\pm$ 1.73
NRS after lidocaine administration (P4)	–	5.83 $\pm$ 0.68	5.83 $\pm$ 0.68
Adverse effects (n)	14 (358%)	2 (33.3%)
	Unpleasant feelings (3, 7.7%),	Dizziness (2, 33.3%)
	dizziness (4, 10.2%),
	drowsiness (7, 179%)
Gabapentin (%)	5 (12.8%)	0 (0%)	5 (11.1%)
Gabapentin dose (mg)	1060 $\pm$ 444.97 (400–1600)		1060 $\pm$ 444.97 (400–1600)
Pregabalin (%)	31 (79.5%)	5 (83.3%)	36 (80%)
Pregabalin dose (mg)	326.61 $\pm$ 152.88 (75–600)	210 $\pm$ 82.16 (150–300)	310.42 $\pm$ 149.93 (75–600)
Tramadol (%)	2 (5.1%)	0 (0%)	2 (4.4%)
Tramadol dose (mg)	150 $\pm$ 70.71 (100–200)		150 $\pm$ 70.71 (100–200)
Acetaminophen/tramadol (%)	14 (35.9%)	2 (33.3%)	16 (35.6%)
Acetaminophen/tramadol dose (mg)	91.07 $\pm$ 24.23 (75–150)	75 (75–75)	89.06 $\pm$ 23.22 (75–150)
Perampanel (%)	22 (56.4%)	2 (33.3%)	24 (53.3%)
Perampanel dose (mg)	3.82 $\pm$ 1.62 (2–8)	3 $\pm$ 1.41 (2–4)	3.75 $\pm$ 1.59 (2–8)
Clonazepam (%)	35 (89.7%)	4 (66.7%)	39 (86.7%)
Clonazepam dose (mg)	0.87 $\pm$ 0.4 (0.25–2)	0.75 $\pm$ 0.29 (0.5–1)	0.86 $\pm$ 0.39 (0.25–2)
Diazepam (%)	4 (10.3%)	1 (16.7%)	5 (11.1%)
Diazepam dose (mg)	2.5 $\pm$ 1.0 (2–4)	2.0 $\pm$ 0.0(2–2)	2.4 $\pm$ 0.89 (2–4)
Lorazepam (%)	13 (33.3%)	4 (66.7%)	17 (37.8%)
Lorazepam dose (mg)	0.65 $\pm$ 0.43 (0.5–2)	3 $\pm$ 1.15 (2–4)	1.21 $\pm$ 1.20 (0.5–4)
Amitriptyline (%)	6 (15.4%)	0 (0%)	6 (13.3%)
Amitriptyline dose (mg)	9.17 $\pm$ 2.04 (5–10)		9.17 $\pm$ 2.04 (5–10)
Baclofen (%)	1 (2.6%)	1 (16.7%)	2 (4.4%)
Baclofen dose (mg)	30 (30–30)	20 (20–20)	25 $\pm$ 7.07 (20–30)
Duloxetine (%)	33 (84.6%)	1 (16.7%)	34 (75.6%)
Duloxetine dose (mg)	49.09 $\pm$ 32.53 (30–120)	30.0 $\pm$ 0.0 (30–30)	48.53 $\pm$ 32.21 (30–120)
Mirtazapine (%)	13 (33.3%)	0 (0%)	13 (28.9%)
Mirtazapine dose (mg)	20.19 $\pm$ 9.87 (7.5–30)		20.19 $\pm$ 9.87 (7.5–30)
Oxycodone (%)	7 (17.9%)	2 (33.3)	9 (20%)
Oxycodone dose (mg)	12.86 $\pm$ 4.88 (10–20)	20.0 $\pm$ 0.0 (20–20)	14.44 $\pm$ 5.27 (10–20)
Tapentadol (%)	5 (12.8%)	0 (0%)	5 (11.1%)
Tapentadol dose (mg)	160 $\pm$ 89.44 (100–300)		160 $\pm$ 89.44 (100–300)
Fentanyl patch (%)	15 (38.5%)	4 (66.7%)	19 (42.2%)
Fentanyl patch dose ( $\mu$ g)	28.1 $\pm$ 13.46 (12–50)	50 (50–50)	28.76 $\pm$ 16.36 (12–50)
Buprenorphine patch (%)	6 (15.4%)	0 (0%)	6 (13.3%)
Buprenorphine patch dose ( $\mu$ g)	6.67 $\pm$ 2.58 (5–10)		6.67 $\pm$ 2.58 (5–10)
Carbamazepine (%)	5 (12.8%)	0 (0%)	5 (11.1%)
Carbamazepine dose (mg)	400.0 $\pm$ 0.0 (400–400)		400.0 $\pm$ 0.0 (400–400)
Quetiapine (%)	9 (23.1%)	5 (83.3%)	14 (31.1%)
Quetiapine dose (mg)	148.61 $\pm$ 148.62 (12.5–400)	147.5 $\pm$ 76.24 (12.5–200)	148.21 $\pm$ 124.02 (12.5–400)
Zolpidem (%)	7 (17.9%)	1 (16.7%)	8 (17.8%)
Zolpidem dose (mg)	10.0 $\pm$ 0.0 (10–10)	6.25 $\pm$ 0.0 (6.25–6.25)	9.53 $\pm$ 1.33 (6.25–10)

Mean $\pm$ standard deviation (minimum to maximum values). Abbreviations: CRPS, complex regional pain syndrome; NRS, numerical rating scale.

Table 2

Initial dose, maximum dose, and duration of intravenous ketamine and lidocaine therapy

	Initial dose (mg)	Maximum dose (mg)	Treatment duration (day)
Ketamine group	46.80 $\pm$ 9.19 (30–67)	90.46 $\pm$ 8.81 (68–108)	9.73 $\pm$ 3.53 (10–19)
Lidocaine group	63.00 $\pm$ 3.10 (60–67)	290.00 $\pm$ 24.50 (240–300)	10.09 $\pm$ 3.24 (4–16)

Mean $\pm$ standard deviation (minimum to maximum values).

Table 3

Changes in the NRS pain scores before and after administration of intravenous ketamine and lidocaine treatment

	NRS score at P1	NRS score at P2	NRS score at P3	NRS score at P4	$P$ -value between periods
Ketamine group	9.83 $\pm$ 0.33 (9–10)	8.32 $\pm$ 1.52 (4–10)	5.20 $\pm$ 1.30 (2–7.5)		P1–P2 P2–P3 P1–P3	$<$ 0.001^* $<$ 0.001^* $<$ 0.001^*
Lidocaine group	9.83 $\pm$ 0.41 (9–10)	8.75 $\pm$ 1.08 (7.5–10)	8.42 $\pm$ 1.28 (7–10)	5.83 $\pm$ 0.68 (5–7)	P1–P2 P1–P3 P1–P4 P2–P3 P2–P4 P3–P4	0.48^* 0.026^* $<$ 0.001^* 0.175 $<$ 0.001^* 0.001^*
Total	9.83 $\pm$ 0.34 (9–10)	8.39 $\pm$ 1.46 (4–10)	5.68 $\pm$ 1.73 (2–10)	5.83 $\pm$ 0.68 (5–7)	P1–P2 P1–P3 P1–P4 P2–P3 P2–P4 P3–P4	$<$ 0.001^* $<$ 0.001^* $<$ 0.001^* $<$ 0.001^* $<$ 0.001^* 0.001^*

Mean $\pm$ standard deviation (minimum to maximum values). Statistical significance was set at $p<$ 0.05. Abbreviations: NRS, numerical rating scale.

3. Results

3.1 Patient characteristics

A total of 45 patients with chronic-stage CRPS were enrolled in this study. Among them, 25 were male and 20 were female (mean age, 51.98 $\pm$ 10.53 years). All patients with chronic CRPS received multimodal oral medications and intravenous ketamine therapy. Among them, six patients with chronic stage CRPS who did not achieve sufficient pain control via multimodal oral medication and intravenous ketamine therapy underwent intravenous lidocaine therapy. The types of oral medications consumed by the patients with CRPS and the doses of each oral medication are presented in Tables 1 and 2.

3.2 Effects of multimodal medication therapy

In all patients with chronic CRPS, the NRS scores after the intravenous lidocaine therapy (P4) demonstrated statistically significant improvements compared to the scores at the initial consultation (P1) ( $p<$ 0.001), after the multimodal oral medication therapy (P2) ( $p<$ 0.001), and after the ketamine treatment (P3) ( $p=$ 0.001). Additionally, in all patients with chronic CRPS, the NRS scores after intravenous ketamine therapy (P3) also demonstrated statistically significant improvements compared to the NRS scores at the initial consultation (P1) ( $p<$ 0.001) and after the multimodal oral medication treatment (P2) ( $p<$ 0.001). Furthermore, in all patients with CRPS, the NRS scores after the multimodal oral medication therapy (P2) also exhibited statistically significant improvements compared to the scores at the initial consultation (P1) ( $p<$ 0.001) (Table 3).

In the ketamine group of patients with chronic-stage CRPS, the NRS scores after the intravenous ketamine or lidocaine therapies (P3) demonstrated statistically significant improvements compared to the NRS scores at the initial consultation (P1) ( $p<$ 0.001) and after the multimodal oral medication therapy (P2) ( $p<$ 0.001). In the ketamine group of patients with CRPS, the NRS scores after the multimodal oral medication therapy (P2) also displayed statistically significant improvements compared to the scores at the initial consultation (P1) ( $p<$ 0.001).

In the lidocaine group of patients with chronic-stage CRPS, the NRS scores after the intravenous lidocaine therapy (P4) displayed statistically significant improvements compared to the pain scores at the initial consultation (P1), after the oral medication therapy (P2) ( $p<$ 0.001), and after the intravenous ketamine therapy (P3) ( $p=$ 0.001). However, the NRS scores after the intravenous ketamine therapy (P3) did not demonstrate any statistically significant improvements compared to the scores following the multimodal oral medication therapy (P2) ( $p=$ 0.175). In contrast, in the lidocaine group, the NRS scores after the multimodal oral medication therapy (P2) demonstrated statistically significant improvements compared to the NRS scores at the initial consultation (P1) ( $p=$ 0.048).

4. Discussion

In this study, we demonstrated the effectiveness of each phase of multimodal medication therapy in patients with chronic CRPS. All three stages, including the administration of multimodal oral medication, intravenous ketamine therapy, and intravenous lidocaine therapy, led to statistically significant improvements in patients with chronic-stage CRPS. Thirty-nine patients with CRPS who underwent intravenous ketamine therapy also displayed statistically significant improvements compared to the NRS scores at the initial consultation and the scores after the administration of the multimodal oral medication. Moreover, six patients with CRPS who underwent intravenous lidocaine therapy displayed statistically improved NRS scores compared to the scores at their initial consultations, after the administration of the multimodal oral medication, and the intravenous ketamine therapy. Furthermore, in both groups with chronic-stage CRPS, the multimodal oral medication also led to statistically significant improvements in NRS scores compared to the initial NRS scores, even though multimodal oral medication therapy alone did not provide sufficient pain control.

The pain caused by CRPS, especially during the acute phase, is associated with peripheral and central neuroinflammation [6]. To address this, oral steroids can be prescribed [9]. Moreover, central neuroinflammation has been correlated with central sensitization. The basic mechanism of central sensitization involves glutamate secretion from the terminals of the spinal dorsal horn and primary sensory neurons, as well as the response of NMDA and AMPA receptors located in the dorsal horn of the spinal cord and primary sensory neurons to the secreted glutamate [20]. Notably, persistent glutamate release can lead to hypersensitivity of the AMPA receptor subunit, thereby increasing the dorsal horn response. This plasticity contributes to the hypersensitivity that underlies pain in the chronic stage of CRPS [20].

As a result of the above, the therapeutic goal for controlling pain in the chronic stage of CRPS is to reduce glutamate secretion from the presynaptic membrane and inhibit the binding of glutamate to AMPA and NMDA receptors in the post-synaptic membrane. The inhibition or blockade of GABA, Ca^{2 +}, alpha-adrenergic, and Na⁺-mediated receptors can decrease or inhibit glutamate secretion in primary sensory neurons. Medications such as baclofen (a GABA_B receptor), clonazepam (a GABA_A receptor), and diazepam (a GABA_A receptor) serve as GABA receptor agonists [11], while gabapentinoids (pregabalin and gabapentin) act as Ca^{2 +} receptor ligands [10]. In parallel, tizanidine and clonidine are alpha-2 adrenergic receptor agonists [21], and carbamazepine and lamotrigine are Na⁺-mediated receptor blockers [13]. Notably, increased interneuronal secretion of serotonin, dopamine, and norepinephrine can reduce glutamate secretion [22]. Therefore, medications such as selective serotonin reuptake inhibitors (fluoxetine or escitalopram), serotonin and norepinephrine reuptake inhibitors (venlafaxine or duloxetine), TCAs (amitriptyline), mirtazapine (enhanced release of serotonin and norepinephrine), and dopaminergic agonists (ropinirole or pramipexole) can be administered to increase serotonin, norepinephrine, and dopamine in the synapses, resulting in a reduction of glutamate secretion [14, 23, 24, 25]. However, the main mechanisms underlying central sensitization may differ among patients with chronic pain [26]. Hence, we administered one medication at a time to each patient and evaluated the effectiveness before administering two or more medications concurrently.

In the course of this study, to block AMPA receptors at the post-synaptic membrane of the dorsal horn of the spinal cord, we used perampanel [16]. Additionally, to control chronic pain refractory to the aforementioned medications, tramadol, acetaminophen/tramadol, or narcotics (oxycodone or tapentadol), which act as $\mu$ -opioid receptor agonists, may be prescribed [17]. In a previous case report, perampanel was reported to be an effective treatment option in patients with chronic-phase CRPS; however, further randomized controlled trials are necessary to confirm the effectiveness and side effects of the medication in patients with CRPS [16]. Additionally, in the present study, all patients with CRPS received an adequate regimen of oral medication; however, their pain did not improve to a tolerable degree. Therefore, all patients with CRPS received intravenous ketamine treatment. Of the 45 patients with CRPS who received both oral medications and intravenous ketamine therapy, six (13.3%) had to undergo intravenous lidocaine therapy for further pain control.

In the past, efforts have been made to control chronic pain using multimodal medications [27]. In 2019, an algorithm titled “The Comprehensive Algorithm for the Management of Chronic Neuropathic Pain” was introduced. This algorithm proposed a structured progression of pain management, ranging from first-line to sixth-line therapies [28]. The algorithm encompassed gabapentinoids, SNRIs, TCAs as first-line treatments, tramadol and tapentadol as second-line treatments, SSRIs, anticonvulsants, NMDA antagonists, and interventional therapy as third-line treatments, neurostimulation as a fourth-line treatment, low-dose opioids as a fifth-line treatment, and targeted drug delivery as a sixth-line treatment. This is very similar to our multimodal oral medication protocol; however, the algorithm includes neurostimulation, which was not employed in our study. Similarly, a consensus statement on the management of chronic neuropathic pain has also been published by the Canadian Pain Society [29]. According to this statement, pharmacological agents are categorized into four lines of management as follows: gabapentinoids, TCAs, and SNRIs as first-line treatments; tramadol and opioid analgesics as second-line treatments; cannabinoids as third-line treatments; and topical lidocaine, methadone (a synthetic opioid), lamotrigine, tapentadol, and botulinum toxin as fourth-line treatments. Notably, this protocol included cannabinoids, botulinum toxin, and topical lidocaine, medications that were not included in our study.

Despite the variety of approaches involving multimodal medication therapy for the management of chronic neuropathic pain outlined above, we integrated intravenous ketamine and lidocaine therapy into our regimen [18, 19]. This addition was made in recognition of the fact that multimodal oral medication alone may not suffice to provide effective pain control. Additionally, to date, few studies have investigated the effectiveness of multimodal medication therapy algorithms in patients with chronic-stage CRPS.

Intravenous ketamine therapy has already been proven to affect pain management in patients with CRPS [18, 30]. Ketamine, a phencyclidine or phenylcyclohexylpiperidine (PCP) derivative, was initially made commercially available for human use in 1970 as a rapid-acting intravenous anesthetic [30]. Moreover, ketamine is currently classified as an anesthetic-inducing agent at doses ranging from 1.0–4.5 mg/kg by the Food and Drug Administration [30]. In addition to the anesthetic effects, ketamine also exhibits anti-inflammatory, analgesic, and antidepressant properties [30]. These characteristics make ketamine a valuable candidate for treating conditions such as CRPS, which typically require a multifaceted approach to management. Currently, three pain societies recommend intravenous dosing of ketamine for chronic pain. This typically involves administering ketamine at a dosage of 0.5 to 2 mg/kg for 1-day outpatient treatment or a more extensive 3- to 5-day inpatient treatment regimen with high doses titrated to effect [31]. In our study, we employed a 1-day treatment approach with a ketamine dosage of 1.4 mg/kg. Another effect of ketamine is that it acts as a noncompetitive antagonist of the PCP-binding site of NMDA receptors in the central nervous system (CNS) [32]. This action leads to a reduction in the frequency of channel opening and the duration of these channels remains in the active open state [32]. In this context, NMDA is a ligand-gated channel whose major endogenous agonist is glutamate, the predominant excitatory neurotransmitter in the CNS [32]. Consequently, the inhibition of NMDA by ketamine results in decreased neuronal activity.

Intravenous lidocaine therapy has also been proven effective for pain management in patients with CRPS [33]. In previous reports, continuousadministration of intravenous lidocaine therapy over 5 days demonstrated that 76% of patients reported at least a 25% reduction in pain, while 31% experienced a greater than 50% pain reduction [34]. Conversely, 24% of patients reported minimal beneficial effects on pain [34]. The side effects associated with this treatment were generally mild, and no severe complications were observed. However, 16 of the 49 (32.6%) patients experienced side effects such as nausea, dizziness, fatigue, tachycardia, and hypotension [34].

Several possible mechanisms underlie the significant and long-lasting effects of prolonged intravenous lidocaine administration in patients with CRPS. Nerve injuries cause changes in the density and location of Na⁺ channels in sensory neurons and decrease their activation threshold and rate of deactivation, which increases Na⁺ currents [35]. These physiological changes may lead to peripheral nociceptive terminal membrane sensitization [36]. Notably, animal models have demonstrated that Na⁺ channels in rat dorsal root ganglion neurons are inhibited by intravenous lidocaine, which may block peripheral sensitization [36]. Peripheral nerve injuries may also maintain a central hyperexcitable state through continuous spontaneous discharges due to abnormal concentrations of Na⁺ channels in the terminal twigs or trunks of injured nerves [37]. Moreover, in cases of tissue injury where small nociceptive afferents are damaged, an inflammatory cascade is associated with the persistent low-frequency spontaneous discharge of A-delta and C-fiber afferents [38]. However, systemic lidocaine can suppress tonic A-delta and C-fiber afferent barrages [39].

Our study had a few limitations. Firstly, due to the retrospective nature of the study and the fact that it was conducted in a single tertiary university hospital, many patients with CRPS could not be enrolled, and the variables affecting pain management could not be completely controlled. Secondly, although various pain patterns are observed in patients with CRPS, we only recorded the NRS score for maximal pain experienced during the day, mainly due to the retrospective nature of the study. Thirdly, a relatively small number of patients with CRPS were enrolled in this study. In the future, improvements according to various pain patterns should be considered, as they may provide insights into the effectiveness of each drug based on the specific pain pattern.

5. Conclusion

Our multimodal medication therapy algorithm, consisting of three main parts(steroid pulse treatment, multimodal oral medication, and intravenous ketamine or lidocaine treatment), was effective in controlling pain in patients with CRPS. These results suggest that achieving effective pain control in patients with CRPS may be challenging when relying solely on one or two medications. For successful pain control, a combination of several therapeutic agents, as presented in our multimodal medication therapy algorithm, is necessary. However, further prospective studies with large sample sizes and randomized controlled trials are needed for more accurate generalization.

Author contributions

Donghwi Park: data analysis, writing the original draft, review, and editing.

Jin-Woo Choi: data acquisition, data analysis.

Min Cheol Chang: writing the original draft, review, and editing.

Data availability statement

The datasets generated during the current study are available from the corresponding author on reasonable request.

Ethical approval

This study was approved by the Institutional Review Board (IRB) of Ulsan University Hospital (IRB number: 22-04-037).

Funding

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. 00219725).

Informed consent

Informed consent was waived due to the retrospective nature of this study.

Footnotes

Acknowledgments

None.

Conflict of interest

The authors report no conflict of interest or financial support.

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Experience from a single-center study on multimodal medication therapy for patients with complex regional pain syndrome

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSIONS:

Keywords

1. Introduction

2. Methods

2.1 Study design and population

2.4 Pain measurement

2.5 Statistical analysis

Table 1 Characteristics of the patients with CRPS

3.1 Patient characteristics

3.2 Effects of multimodal medication therapy

4. Discussion

5. Conclusion

Author contributions

Data availability statement

Ethical approval

Funding

Informed consent

Footnotes

Acknowledgments

Conflict of interest

References

Table 1
Characteristics of the patients with CRPS