Abstract
Background:
A new peptide analgesic, a highly selective μ1-opioid receptor agonist (Taphalgin®) has shown the high efficacy in treating acute postoperative and chronic oncological pain, it appears to be a promising option for the treatment of patients with severe pain in outpatient clinics.
Methods:
Prospective observational study with a control period 4 hours after a single injection. The onset and peak of the analgesic effect, duration of effect, patient satisfaction and tolerability of therapy were assessed.
Results:
A total of 37 patients participated in the study. The pain intensity before the injection was 8.9 ± 1.2 according to numeric rating scale. Causes of severe pain included: radicular, oncologic and lumbar pain, vertebral fractures, joint injuries, tendon ruptures and others (e.g., hip fracture, nerve injury). Up to 95% of patients were already receiving pain therapy from non-steroidal anti-inflammatory drugs to strong opioids. After injection, pain intensity decreased with a peak at 30-45 minutes from 8.9±1.2 to 3.2±2.8 (P ≤ 0.0001) points on numeric rating scale and lasted for more than 3 hours. There was no difference in pain intensity at rest and with movement. Adverse events were reported in 19 of 37 patients (51.3%). Most adverse events were non-serious, did not require treatment and resolved on their own.
Conclusions:
The μ1-opioid receptor agonist Taphalgin® demonstrates high efficacy, ease of use, rapid onset of effect and good tolerability in patients with severe pain syndrome in outpatient settings.
Keywords: Acute pain, ambulatory care, oligopeptides, pain management
Introduction
Intense pain syndromes (seven points or higher on the numerical rating scale) are common reasons for seeking outpatient care.[1,2] In outpatient settings, intense pain can significantly complicate examinations and affect the choice of diagnostic and treatment approaches, potentially impacting disease prognosis. This conditions a need for a medication with rapid and pronounced analgesic effects, convenient administration methods (oral, subcutaneous, intramuscular), and minimal side effects.
Currently, there are various drug classes capable of providing rapid analgesia, including traditional non-steroidal anti-inflammatory drugs (NSAIDs), opioids, local anesthetics, and general anesthesia agents. The mechanisms of action and efficacy of these drugs can vary significantly. However, most traditional analgesics have specific and non-specific side effects and contraindications that may limit their use.[3] In recent years, peptide analgesics, which act through the selective interaction with specific receptors, involved in pain signal modulation, have been actively researched. This selectivity allows for high therapeutic effectiveness with minimal side effects.
A new peptide analgesic—a highly selective agonist of μ1-opioid receptors (Taphalgin®)—was registered on the Russia in 2022. The active compound is tyrosyl-D-arginyl-phenylalanyl-glycine amide. The drug has shown high efficacy in treating acute postoperative and chronic oncological pain.[4,5] The drug not only provided effective pain relief but also demonstrated excellent tolerability and the absence of serious side effects, making it a promising option for managing patients with intense pain in an outpatient setting.
The aim of this study is to evaluate the effectiveness and tolerability of the peptide analgesic Taphalgin® for treating intense pain in an outpatient clinic.
Materials and Methods
Study design, setting and eligibility criteria
This was an open, observational, non-randomized, uncontrolled study conducted at the outpatient pain management clinic. The study was approved in accordance with the ethical principles of the Helsinki Declaration of the WMA “Ethical Principles for Medical Research Involving Human Subjects” (64th WMA General Assembly, Fortaleza, Brazil, October 2013) by the Institutional ethics committee.
Patients seeking help during outpatient visits were included in the study from September 2023 to July 2024. The sample size was not predetermined and was dictated by the length of the study. Inclusion criteria for the study were as follows: age from 18 to 90 years, pain syndrome of medium to high intensity, more than five points on the NRS, signed informed consent form by the patient. Exclusion criteria: hypersensitivity to the active substance or any of the excipients, alcohol, psychoactive drugs, or opioid intoxication, pregnant or breastfeeding women, patients who had previously used Taphalgin®, refusal of the patient to participate in the study.
Taphalgin® was administered as a single-shot subcutaneous injection in a dose 7 mg. The observation period was 4 hours post-injection, with intensity assessments before the injection and at 15, 30, 45, 60, 120, 180, and 240 min after injection with numeric rating scale (NRS). The onset and peak of analgesic effect, duration of effect, and therapy tolerability were assessed. Patient satisfaction with the treatment outcome was rated on a five-point scale: 0 - abstained, 1 - very poor, 2 - unsatisfactory, 3 - satisfactory, 4 - good, 5 - excellent. The effectiveness of pain relief was also assessed by evaluating the percentage of patients with a good outcome, defined as the proportion of patients, whose pain intensity did not exceed three on the NRS scale one hour after injection.
Statistical processing was carried using Statistica 8.0 for Windows and included descriptive statistics, paired Student’s t-test, and Mann-Whitney U test.
Results
A total of 37 patients participated in the study (16 men and 21 women). The average age was 60.7 ± 16.2 years (range 33 to 87 years), and the average body mass index (BMI) was 28.7 ± 7.7 (range 13.7 to 60). The duration of intense pain prior to study enrollment averaged 19.0 weeks (range 1 day to 3 years), and the intensity of pain prior to injection was 8.9 ± 1.2 from 5 to 10 points on the NRS. In 24% of the patients (nine patients), a neuropathic component of pain (>4 points on the DN4) was noted. The distribution of pain syndromes by etiology is shown in Table 1.
Table 1.
Distribution of pain syndromes by etiology
| Etiology | Number of Patients |
|---|---|
| Radicular Pain | 16 (43%) |
| Oncological Pain | 8 (22%) |
| Low Back Pain | 2 (5%) |
| Vertebral Body Fractures | 3 (8%) |
| Joint Injury, Tendon Rupture | 4 (11%) |
| Other (e.g., hip neck fracture, nerve injury) | 4 (11%) |
Prior to inclusion in the study, 95% of patients had already received analgesic therapy, shown in Table 2.
Table 2.
Previous analgesic therapy
| Previous Therapy | Number of Patients |
|---|---|
| None | 2 (5%) |
| NSAIDs + Adjuvants | 27 (73%) |
| Weak Opioids (tramadol, tapentadol) | 7 (19%) |
| Strong Opioids (fentanyl) | 1 (3%) |
Overall, the use of Taphalgin® as emergency aid for patients with intense pain resulted in a significant reduction of pain intensity within 17 min, reaching a peak from 8.9 ± 1.2 to 3,2±2.8 (p≤0,0001) NRS points at 30-45 minutes post-injection and lasting for more than 3 hours [Figure 1 Intensity of pain during movement before and after injection - NRS points]. There was no significant difference in pain intensity at rest and during movement.
Figure 1.
Intensity of pain during movement before and after injection (NRS points)
Good pain relief results (pain intensity not exceeding 3 on the NRS scale) were achieved in 76% of patients 1 hour after injection. Complete pain relief was achieved in 10 (27%) patients, while in one case (2.7%) there was no relief at all.
The mean satisfaction score with the analgesia was 3.95 ± 1.15 (range 1 to 5), [Figure 2 Subjective assessment of therapy effectiveness].
Figure 2.
Subjective assessment of therapy effectiveness
Adverse Events: Adverse events were reported in 19 out of 37 patients (51.3%). Most adverse events were not serious, did not require treatment, and resolved on their own [Table 3].
Table 3.
Adverse events during therapy with Taphalgin®
| Adverse Event | Treatment | Number of Patients (%) |
|---|---|---|
| Brain fog and/or dry mouth | Monitoring only, no treatment needed | 13 (35.1%) |
| Nausea/Dizziness/Facial Flushing/Agitation | 2 (5.4%) | |
| Orthostatic Hypotension | 3 (8.1%) | |
| Vascular Collapse | Anticholinergic therapy, IV infusion, O2 insufflation | 1 (2.7%) |
A detailed analysis of orthostatic reactions retrospectively revealed no correlation between anthropometric data, diseases, or ongoing therapy [Table 4]. However, a high likelihood of accidental intramuscular administration was identified in all four cases of decreased blood pressure. After correcting injection technique, no further incidents of orthostatic reactions were noted.
Table 4.
Patients with orthostatic reaction post-Taphalgin® injection
| Age | Gender | BMI | Pain Cause | Comorbidity | Medications |
|---|---|---|---|---|---|
| 55 | M | 22.7 | Post-injection Sciatic Neuropathy | Hip Avascular Necrosis | No matches |
| 33 | M | 60 | Lumbar Radicular Pain | Obesity | |
| 79 | F | 39 | Shoulder Trauma, Adhesive Capsulitis | Hypertension, Diabetes type 2 | |
| 70 | F | 26.6 | Sacrum Fracture | Hypertension, Kidney Disease, Rheumatoid Arthritis, Osteoporosis, Aortic Aneurysm |
Discussion
One promising direction in pain relief therapy is the effect of peptide analgesics on ionotropic purinergic receptors P2X. These receptors are ligand-gated ion channels activated by adenosine triphosphate (ATP) and its derivatives. Convincing evidence suggests that the P2X3 and P2X2/3 subtypes play significant roles in pain signal transmission. These receptors are localized in peripheral nerve terminals and dorsal root ganglion neurons, present on thinly myelinated Aδ and unmyelinated C fibers, involved in pain signal transmission from the skin, joints, muscles, and internal organs,[6] and are also found in the brainstem, where they contribute to the release of glutamate and substance P involved in pain signal transmission.[7] In recent years, the analgesic properties of peptides acting on these receptors, such as AF-353 and PT-1, have been actively explored.[8,9] Another promising peptide analgesic is the thioredoxin protein APH, an antagonist of the TRPV1 receptors, involved in pain signal conduction and temperature sensitivity.[10] Experiments have shown this drug to exhibit more pronounced analgesic activity compared to non-peptide TRPV1 antagonists.[11] Omega-conotoxin, known as ziconotide, is another example of a peptide analgesic successfully used for alleviating acute and chronic pain.[12]
In 2022, an innovative tetrapeptide analgesic, tyrosyl-D-arginyl-phenylalanyl-glycine amide, was registered in Russia, marketed as Taphalgin®. Its primary effect occurs at the level of the dorsal horns of the spinal cord, an area with the highest concentration of μ1-opioid receptors. Binding of Taphalgin® molecules to the receptors initiates the release of a G-protein complex, which activates the closing of calcium channels and opening of sodium channels, reducing the level of cyclic adenosine monophosphate (cAMP). This suppresses excitation in nociceptors and decreases the release of pain mediators, involved in peripheral pain signal transmission. The action of Taphalgin® on central pain modulation mechanisms enhances its antinociceptive activity and suppresses pain perception.[13] The high affinity of Taphalgin® for μ1-opioid receptors and the reversibility of this binding provide high analgesic activity and the absence of cumulative side effects. Due to the selectivity of the tyrosyl-D-arginyl-phenylalanyl-glycine amide molecule for µ-1 receptors, the use of Taphalgin® does not lead to the activation of µ-2 receptors typical for classical opioid analgesics. According to the instructions and clinical studies conducted, the use of Taphalgin® does not cause life-threatening side effects characteristic of opioid drugs such as respiratory and cardiac suppression.[4,5,13,14,15,16] To date, it is considered that the use of Taphalgin® does not require monitoring of vital functions. However, the analgesic effect of the drug is comparable to morphine, as shown by the results of a multicenter controlled study dedicated to evaluating its effectiveness and safety in treating oncological pain.[4] The properties of Taphalgin® explain the interest in using the drug also for emergency analgesia in outpatient practice.
Taphalgin® is available as an injection solution and is strictly administered subcutaneously. In our study, a moderately severe adverse event in the form of clinically significant arterial hypotension was observed, which manifested clinically when the patient was in an upright position. All previous studies on the effectiveness and safety of Taphalgin® were conducted in inpatient settings, but there is no data on whether patients who used Taphalgin® were confined to bed. It can be presumed that administering the drug while the patient is seated increases the risk of orthostatic reaction, and incorrect injection technique makes such a complication quite likely. As a preventive measure for such complications, it is currently recommended that patients maintain a horizontal position for 30–60 min post-injection and monitor blood pressure.
Conclusions
The μ1-opioid receptor agonist Taphalgin® demonstrates high efficacy and good tolerability in patients with intense pain syndrome in outpatient settings. The simplicity of its use and the rapid onset of effect make it recommendable for emergency analgesia for patients requiring diagnostic or invasive procedures, provided that the application technique is followed according to the manufacturer’s recommendations.
Conflicts of interest
There are no conflicts of interest.
Funding Statement
Nil.
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