Efficacy and Safety of Intravenous Dexamethasone Palmitate Treatments in Acute and Subacute Herpes Zoster Pain

Herpes zoster (HZ), commonly known as shingles, is a painful condition caused by the reactivation of the varicella-zoster virus (VZV). It typically presents as a unilateral, dermatomal vesicular rash accompanied by severe pain descriptors such as burning, prickling, and electric shock-like sensations. The global incidence of HZ ranges from 2 to 5 per 1000 person-years, with a sharp increase to 5.77-9.85 per 1000 person-years after the age of 50, representing a significant public health burden.

The pain associated with HZ, termed Zoster-Associated Pain (ZAP), progresses through distinct phases: the prodromal phase (1-5 days before rash), the acute phase (≤30 days after rash onset), and the subacute phase (31-89 days after rash onset). The most debilitating complication is Postherpetic Neuralgia (PHN), defined as pain persisting for 90 days or more after rash onset. PHN affects approximately 30% of HZ patients and can persist for years, severely diminishing quality of life. A cornerstone of HZ management is the early and aggressive treatment of acute and subacute ZAP to achieve symptomatic relief and potentially prevent the transition to the chronic neuropathic pain state of PHN.

The pathophysiology of ZAP evolves over time. Acute ZAP is predominantly nociceptive, driven by viral replication-induced inflammation, hemorrhagic necrosis of dorsal root ganglia, and tissue edema causing nerve compression. As the disease progresses, peripheral and central sensitization occur, leading to neuropathic pain. Current European guidelines recommend initiating antiviral therapy (e.g., famciclovir) within 72 hours of rash onset to limit viral replication. Pharmacological management of pain typically includes non-opioid analgesics (e.g., NSAIDs like celecoxib), opioid analgesics (e.g., tramadol), and analgesic adjuncts like gabapentin or pregabalin. However, these conventional therapies have limitations, including side effects (gastrointestinal, neuropsychiatric, renal, hepatic) and a limited impact on preventing PHN.

The role of corticosteroids in HZ management remains controversial. Given that inflammation is a key driver of acute pain and neural damage, corticosteroids' potent anti-inflammatory properties are theoretically beneficial. A meta-analysis of systemic corticosteroids (e.g., prednisone) showed efficacy in relieving acute pain but no significant effect on PHN prevention. Furthermore, systemic corticosteroids are associated with well-documented risks, including hyperglycemia, hypertension, weight gain, and gastrointestinal issues. Consequently, current evidence does not support the routine use of systemic corticosteroids for ZAP due to an uncertain risk-benefit profile.

Dexamethasone Palmitate (DXP) is a lipophilic prodrug of dexamethasone with unique pharmacological properties. It has a long biological half-life (36-72 hours) and high lipid solubility. This allows it to be preferentially taken up by phagocytic cells and targeted to sites of inflammation, leading to higher local concentrations and potentially reduced systemic exposure compared to traditional corticosteroids. This targeted action may translate into enhanced efficacy and a more favorable safety profile. Previous studies have explored the use of DXP in local nerve blocks for ZAP, demonstrating promise. However, these procedures are technically demanding, require ultrasound guidance, and carry risks of tissue injury, limiting their widespread applicability.

This study aims to address a critical evidence gap by investigating the efficacy and safety of systemically administered DXP (intramuscular and intravenous) as a more accessible alternative to complex nerve blocks. Furthermore, it will directly compare systemic administration with localized techniques (tender point infiltration, paravertebral, and trigeminal nerve blocks) across different patient populations (spinal and trigeminal nerve HZ) and doses. The overarching hypothesis is that DXP, by effectively controlling early inflammation through various administration routes, will provide superior pain relief and reduce the incidence of PHN compared to standard therapy alone, with an acceptable safety profile.

1.2. Objective

The primary objective of this series of studies is to evaluate the efficacy of different administration routes and doses of Dexamethasone Palmitate (DXP), in combination with standard therapy, versus standard therapy alone, in reducing pain intensity in patients with acute and subacute Herpes Zoster.

The study consists of four distinct but parallel sub-studies:

Study 1: To compare the efficacy of systemic DXP administration (Intramuscular vs. Intravenous injection) against a control group receiving standard therapy.

Study 2: To compare the efficacy of two different intravenous doses of DXP (4 mg vs. 8 mg) against a control group.

Study 3: To compare the efficacy of different injection techniques (Intramuscular vs. Tender Point Infiltration vs. Paravertebral Injection) for HZ affecting spinal nerves (trunk).

Study 4: To compare the efficacy of different injection techniques (Intramuscular vs. Tender Point Infiltration vs. Trigeminal Nerve Block) for HZ affecting the trigeminal nerve (face).

Secondary objectives include:

To compare the incidence of Postherpetic Neuralgia (PHN) at 3 and 6 months post-treatment among the intervention groups.

To assess the consumption of rescue analgesics (celecoxib, tramadol) over time.

To evaluate the consumption of pregabalin over time.

To assess patient satisfaction with the treatment.

To evaluate changes in health-related quality of life (HRQoL).

To monitor and compare the safety and tolerability profiles of all intervention strategies.

1.3. Study Design

Overall Design: This is a prospective, randomized, multicenter, open-label, controlled trial with a blinded endpoint assessment (PROBE design). The trial comprises four independent sub-studies, each with a parallel-group design.

Key Design Features:

Randomization: Participants will be randomly assigned to their respective study groups using a computer-generated random number sequence created with Statistical Package for the Social Sciences (SPSS) version 25.0. Randomization will be stratified by study center to ensure balance across groups for factors like disease duration, baseline pain intensity, and affected dermatome. The allocation ratio is 1:1:1 in all four sub-studies.

Blinding (Masking): This is an open-label study for the treating physicians and patients due to the obvious differences between systemic injections and local procedures. However, to minimize assessment bias, the endpoint is blinded. Specifically, the physicians responsible for post-treatment evaluations during follow-up, the outcome assessors, and the data analysts will be blinded to the treatment group assignments. The operators performing the injections are not involved in any follow-up assessments or data analysis.

Duration: The intervention is a single administration (or a short series for some local techniques). The total study duration for each participant will be approximately 6 months, involving follow-up assessments at Week 1, Week 2, Month 1, Month 3, and Month 6.

Sub-Study Structures:

Study 1 (Systemic Route Comparison):

Group 1: Control Group (n=59): Standard antiviral therapy + Pregabalin + Rescue analgesics.

Group 2: IM Group (n=59): Standard antiviral therapy + Single IM injection of DXP 8 mg + Pregabalin + Rescue analgesics.

Group 3: IV Group (n=59): Standard antiviral therapy + Single IV infusion of DXP 8 mg + Pregabalin + Rescue analgesics.

Study 2 (Intravenous Dose Comparison):

Group 1: Control Group (n=44): Standard antiviral therapy + Pregabalin + Rescue analgesics.

Group 2: 4mg Group (n=44): Standard antiviral therapy + Single IV infusion of DXP 4 mg + Pregabalin + Rescue analgesics.

Group 3: 8mg Group (n=44): Standard antiviral therapy + Single IV infusion of DXP 8 mg + Pregabalin + Rescue analgesics.

Study 3 (Spinal Nerve HZ - Injection Techniques):

Group 1: IM Group (n=43): Standard antiviral therapy + Single IM injection of DXP 8 mg + Pregabalin + Rescue analgesics.

Group 2: TPI Group (n=43): Standard antiviral therapy + Tender Point Infiltration with DXP 8 mg + 1% Lidocaine + Pregabalin + Rescue analgesics.

Group 3: PI Group (n=43): Standard antiviral therapy + Paravertebral Nerve Block with DXP 8 mg + 1% Lidocaine + Pregabalin + Rescue analgesics.

Study 4 (Trigeminal Nerve HZ - Injection Techniques):

• PHN incidence [Срок оценки: month 3 and month 6]