Postoperative analgesic efficacy of pharmacopuncture at Zusanli (ST-36) or intramuscular morphine in bitches undergoing unilateral total mastectomy: a randomized clinical trialABSTRACT
This study aimed to compare the postoperative analgesic efficacy of intramuscular morphine and morphine pharmacopuncture at the Zusanli acupoint (ST-36) in female dogs undergoing unilateral total mastectomy. Sixteen client-owned bitches were randomly assigned to a double-blinded clinical trial and received either intramuscular morphine (0.5mg/kg; MORP) or pharmacopuncture with a microdose of morphine (0.05mg/kg) at ST-36 (ZUS36). Pain assessments were conducted at T0-T24 hours using the Visual Analog Scale (VAS) and the short-form Glasgow Composite Pain-Scale (CMPS-SF), evaluated by an experienced (EE) and a non-experienced assessor (NEE). Both protocols provided effective analgesia, with no significant differences in postoperative pain scores. The number of rescue interventions based on VAS assessments was 8 for MORP and 6 for ZUS36, while CMPS-SF evaluations recorded 15 and 13 interventions, respectively, for EE. The NEE overestimated rescue analgesia requirements in VAS assessments (11 rescues for MORP vs. 7 for ZUS36) but underestimated them in CMPS-SF evaluations (13 for MORP vs. 11 for ZUS36). A strong correlation was observed between EE and NEE in CMPS-SF (r=0.940) and VAS (r=0.748). Pharmacopuncture at ST-36 provided analgesia comparable to intramuscular morphine, highlighting its potential as an adjuvant analgesic strategy to reduce opioid requirements in canine mastectomy.
Keywords:
analgesia; pharmacopuncture; visual analog scale; Zusanli
RESUMO
Objetivou-se comparar a eficácia analgésica pós-operatória da morfina intramuscular e da farmacopuntura com morfina no ponto de acupuntura Zusanli (ST-36), em cadelas submetidas à mastectomia total unilateral. Dezesseis cadelas foram randomizadas para um ensaio clínico duplo-cego e receberam morfina intramuscular (0,5mg/kg; MORP) ou farmacopuntura com uma microdose de morfina (0,05mg/kg) no ST-36 (ZUS36). A avaliação da dor foi realizada entre T0 e T24 horas, utilizando-se a escala visual analógica (VAS) e a versão reduzida da escala composta de dor de Glasgow (CMPS-SF), analisadas por um avaliador experiente (EE) e um avaliador não experiente (NEE). Ambos os protocolos proporcionaram analgesia eficaz, sem diferenças significativas nos escores de dor pós-operatória. O número de intervenções analgésicas de resgate com base na VAS foi de oito para o grupo MORP e de seis para o grupo ZUS36, enquanto as avaliações pela CMPS-SF registraram 15 e 13 intervenções, respectivamente, para o EE. O NEE superestimou a necessidade de resgate analgésico nas avaliações pela VAS (11 resgates para MORP vs. sete para ZUS36), mas subestimou na CMPS-SF (13 para MORP vs. 11 para ZUS36). Foi observada uma forte correlação entre EE e NEE na CMPS-SF (r=0,940) e na VAS (r=0,748). A farmacopuntura no ST-36 demonstrou analgesia comparável à morfina intramuscular, destacando seu potencial como estratégia analgésica adjuvante para reduzir a necessidade de opioides na mastectomia em cães.
Palavras-chave:
analgesia; correlação; farmacopuntura; Zusanli
INTRODUCTION
Mastectomy is frequently required in small animal practice because of the high incidence of malignant mammary tumors, mainly in intact female dogs (Sleeckx et al., 2011). Surgical excision may vary in extent, encompassing lumpectomy, simple mastectomy, regional mastectomy, and unilateral or bilateral chain mastectomy, the latter involving en bloc resection of all mammary glands on both sides of the thoracoabdominal wall (MacPhail and Fossum 2018). As ovarian hormones play an important role in the etiology of canine mammary carcinomas, ovariohysterectomy (OE) at the time of mastectomy has also been recommended to reduce the risks of future development of other mammary tumors (Kristiansen et al., 2016).
Opioid-based analgesia is usually prescribed for the perioperative pain management of canine mastectomy with or without OE. (Teixeira et al., 2013; Minto et al., 2013). However, negative immunomodulatory effects have been associated with some opioid agents, leading to hesitations regarding their use in cancer patients (Boland and Pockley 2018). In addition to these concerns, opioids may cause dose-dependent adverse effects, including vomiting, respiratory depression, urinary retention, excitement/dysphoria, and histamine release (Paul et al., 2021).
Acupuncture may be an alternative to avoid the adverse effects of opioids in acute and chronic pain management (Luna et al., 2015). This technique has been successfully used in animals to treat neurological syndromes and musculoskeletal diseases that result in pain (Luna et al., 2015). A possible alternative is the injection of substances or micro-clinical doses of drugs into acupoints, known as pharmacopuncture. This method combines traditional acupoint stimulation with the local delivery of a pharmacological agent, which is believed to potentiate and prolong the drug effect (Luna et al., 2015; Ariga et al., 2025). Pharmacopuncture has been successfully applied for sedation in horses (Luna et al., 2008), and recent studies have shown that pharmacopuncture using metamizole provides analgesic effects comparable to intramuscular administration of the same drug (Ariga et al., 2025). Defined as the injection of low doses of drugs or small amounts of medicinal extracts into acupuncture points, pharmacopuncture represents an alternative method to stimulate acupoints (Luna et al., 2015).
Studies have focused on the use of nonpharmacological therapies as part of a multimodal analgesic approach, including classical acupuncture and related techniques, to improve perioperative analgesia and reduce anesthetic and opioid requirements in small animals (Groppetti et al., 2011; Gakiya et al., 2011).
This study aimed to evaluate the postoperative analgesic effect of intramuscular morphine in comparison with morphine pharmacopuncture at the acupuncture point Stomach 36 (ST36, Zusanli) in female dogs undergoing unilateral total mastectomy. Additionally, this study assessed postoperative pain using the Visual Analog Scale (VAS) and the short form of the Glasgow Composite Pain Scale (CMPS-SF), comparing evaluations performed by an experienced and a non-experienced assessor.
ETHICAL ASPECTS
The study was approved by the Ethics Committee on Animal Use of the State University of Santa Catarina (UDESC) under protocol number 1.15.15.
MATERIAL AND METHODS
This double-blinded, randomized, parallel-group clinical trial with balanced randomization (1:1) was conducted at Santa Catarina State University (UDESC) and received approval from the Animal Ethics Committee under protocol number 1.15.15.
Only animals classified as American Society of Anesthesiologists (ASA) physical status II or III were included, confirmed through clinical and laboratory examinations, as well as electrocardiography and thoracic radiography performed one week before the study. Health screening included a physical examination and hematological and biochemical analysis of blood samples. Dogs exhibiting consistent aggressive behavior, cardiovascular alterations detected via electrocardiogram, or lung metastases identified through chest radiography were excluded. Additionally, animals with ulcerated mammary tumors or presenting behavioral traits that would hinder postoperative evaluations were not included. Food was withheld for approximately 8 hours prior to general anesthesia, while water remained available. On the day of the procedure, the dogs were transported to the surgical center and returned to the hospital ward after complete recovery.
The animals were hospitalized 24 hours prior to the surgical procedure for acclimatization to the hospital environment. All anesthetic procedures were performed by a single anesthesiologist. Preanesthetic medication, consisting of acepromazine (0.02 mg/kg; Acepran 0.2%, Vetnil, SP, Brazil) and morphine (0.5 mg/kg; Dimorf 10 mg/mL, Cristália, SP, Brazil), was administered intramuscularly into the semitendinosus/semimembranosus muscles. After 15 minutes, sedation scores were assessed using the scale described by Alvaides et al. (2008). An intravenous catheter was placed in a cephalic vein, and arterial cannulation was performed using a 20- or 22-gauge venous catheter (Safelet-ETFE) for subsequent induction of general anesthesia. Propofol (10 mg/mL; Cristália) was administered intravenously to effect (1 mg/kg every 30 seconds), and orotracheal intubation was performed once the animal exhibited loss of jaw tone and absence of the swallowing reflex.
Immediately after anesthetic induction, a bolus of ketamine (2.5mg/kg) and fentanyl (2.5µg/kg) was administered intravenously. Intraoperative analgesia was maintained through a continuous infusion rate (CRI) of ketamine and fentanyl at rates of 10µg/kg/min and 10µg/kg/h, respectively. This infusion was discontinued immediately upon completion of the surgical procedure. Lactated Ringer's solution (Lactate Ringer 500 mL; Cristália, SP, Brazil) was infused intravenously at a rate of 5 mL/kg/h using an infusion pump (ST1000; Samtronic, SP, Brazil) during all anesthetic procedure.
Mechanical ventilation was initiated using a pressure-cycled ventilator (9100c; GE Healthcare Datex-Ohmeda). General anesthesia was maintained with isoflurane (1 MAC) in 100% oxygen, under pressure-controlled mechanical ventilation set at 12 cmH₂O, with a respiratory rate of 12 breaths per minute and an inspiration-to-expiration ratio of 1:2, aiming to maintain normocapnia (35-45 mmHg). The animals were positioned in dorsal recumbency for the unilateral total mastectomy procedure, which was consistently performed by the same surgeon.
In the immediate postoperative period, meloxicam (0.2 mg/kg) was administered intravenously. Subsequently, the animals were randomized into three different postoperative analgesic treatment groups. Pain assessments were performed, and the animals received their respective treatments accordingly.
Postoperative evaluations were conducted by two assessors: an experienced evaluator (EE) and a non-experienced evaluator (NEE). The animals' behavior was assessed at baseline (T0) and at predetermined time points after extubation: 1 (T1), 2 (T2), 4 (T4), 6 (T6), 8 (T8), 12 (T12), and 24 (T24) hours post-extubation. These assessments utilized the visual analog scale (VAS, from 0 mm = no pain to 100 mm = maximum pain) and the short form of the Glasgow Composite Pain Scale (CMPS-SF, from 0 = no pain to 24 = maximum pain) (Reid et al., 2007). The process began with the VAS, which involved observing the patient without interaction, followed by the CMPS-SF assessment, which included interaction with the patient. Immediately after the evaluations, the animals underwent fasting protocols of 12 hours for food and 6 hours for water.
Immediately after extubation, morphine was administered according to the assigned treatment group. Animals in the intramuscular morphine group (MORP, n=8) received postoperative rescue morphine at a dose of 0.5 mg/kg, administered intramuscularly. In the morphine pharmacopuncture group (ZUS36, n=8), morphine was administered at a dose of 0.05 mg/kg at the acupuncture point Stomach 36 (ST36, Zusanli), ipsilateral to the surgical site. This acupoint is located approximately 3 cun [1 cun = width of the last rib] or about 5 cm distal to the head of the fibula, lateral to the crest on the lateral surface of the tibia (Figure 1). Subsequent rescue analgesia was determined based on pain assessment scales. If VAS and/or CMPS-SF scores reached or exceeded 30 mm and ≥ 6 points, respectively, as assessed exclusively by the experienced evaluator, rescue analgesia was administered. The number of animals requiring rescue analgesia was recorded.
For all acupuncture-based rescue techniques, the final syringe volume was standardized to 1mL, with the calculated dose adjusted using 0.9% saline solution as necessary. All postoperative rescue analgesia was administered by the same veterinary acupuncturist, following the specific methodology assigned to each group (MORP or ZUS36).
Data were analyzed using SigmaPlot 12.0 and GraphPad Prism 9.3. Normality was assessed using the Shapiro-Wilk test. Parametric data were analyzed using the t-test for group comparisons (e.g., weight, age) and one-way ANOVA followed by Tukey’s test for time-point comparisons within groups. For non-parametric data, the Friedman test, followed by Tukey’s test, was used for time-point comparisons within the same group, while the Mann-Whitney U test was applied for intergroup comparisons. A p-value of ≤ 0.05 was considered statistically significant.
Postoperative rescue analgesia between evaluators was analyzed using Kaplan-Meier survival analysis and the Log-rank test to assess differences in rescue occurrences. The Wilcoxon signed-rank test was used for paired comparisons. Furthermore, the correlation between the pain scale results was assessed using Pearson’s correlation test assessed the consistency between the scores given by two assessors: experienced (EE) and a non-experienced assessor (NEE), using Visual Analog Scale (VAS) and the short-form Glasgow Composite Pain Scale (CMPS-SF) interpreted according to Evans (1996) as follows: very weak (r = 0.00-0.19), weak (r = 0.20-0.39), moderate (r = 0.40-0.59), strong (r = 0.60-0.79), and very strong (r = 0.80-1.00). Results were considered statistically significant at p < 0.05.
CASUISTRY
The study enrolled 16 mixed-breed female dogs scheduled for mastectomy, all owned by private individuals who provided informed written consent prior to participation. The sample size was calculated using statistical software (OpenEpi, version 3.0; OpenEpi, TN, USA) with an alpha level of 5% (two-sided), beta of 20% (80% power), and an assumed clinically significant reduction in postoperative rescue analgesia of 20%. Based on these parameters, 16 animals were deemed necessary to detect this difference, with the animals randomly allocated in a randomized and blinded manner (1-1), using the software available at www.randomization.com, into two study groups: intramuscular morphine group (MORP, n=8) or morphine pharmacopuncture group (ZUS36, n=8). Acupuncture procedures were conducted following the guidelines outlined in the Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) to ensure methodological rigor in clinical studies.
RESULTS
A total of 24 dogs were screened for enrollment; however, 8 did not meet the inclusion criteria (6 due to pulmonary metastasis and 2 due to cardiac conditions). Thus, 16 animals successfully completed the study.
The study population demonstrated homogeneity in terms of age (MORP: 8.63 ± 2.88 years; ZUS36: 9.63 ± 2.62 years; p = 0.4788), body mass (MORP: 15.65 ± 8.56kg; ZUS36: 11.20 ± 12.21kg; p = 0.4111), and surgical duration (MORP: 58.1 ± 26.6 minutes; ZUS36: 78.2 ± 41.21 minutes; p = 0.5199).The sedation scores (Table 1) indicated significantly higher values in the intramuscular morphine group (MORP) between T1 and T4 compared to baseline (T0), with statistical significance at p = 0.0268, p = 0.0212, and p = 0.0314, respectively. Additionally, sedation scores differed significantly between treatment groups at T1 (p = 0.042) and T2 (p = 0.00212).
Postoperative pain scores were assessed using both the Visual Analog Scale (VAS) and the short form of the Glasgow Composite Pain Scale (CMPS-SF) showed no statistically significant differences between treatment groups (Table 2). However, the need for rescue analgesia was observed within the first postoperative hour in both groups, persisting up to 8 hours postoperatively. Although no statistical differences were found between the two scales, the pharmacopuncture group (ZUS36) consistently exhibited lower pain scores compared to the intramuscular morphine group (MORP).
Rescue analgesia assessments (Fig. 2) performed by the experienced evaluator recorded a total of 8 rescues in the MORP and 6 rescues in the ZUS36 based on VAS scores, with no significant difference between groups (p = 0.3821). Similarly, CMPS-SF evaluations indicated 15 rescues for MORP and 13 for ZUS36, also without statistical significance (p = 0.4181).
For the non-experienced evaluator (Table 2), a similar distribution was observed. However, in the VAS assessment, the non-experienced evaluator overestimated the need for rescue analgesia, recording 11 rescues in the MORP and 7 in the ZUS36 (p = 0.1821). In contrast, CMPS-SF evaluations by the non-experienced evaluator underestimated rescue occurrences, reporting 13 rescues in the MORP and 11 in the ZUS36 (p = 0.3361).
Regarding the overall correlation (Table 3), a very strong correlation was observed between the experienced evaluator (EE) and the non-experienced evaluator (NEE) for CMPS-SF (r = 0.940), while a strong correlation was found between EE and NEE for VAS (r = 0.748). Additionally, when comparing VAS and CMPS-SF scores, the NEE demonstrated a strong correlation (r = 0.772), whereas the EE exhibited a very strong correlation (r = 0.812).
Total Number of Rescue Analgesia Interventions at Each Time Point in Dogs Receiving Intramuscular Morphine (0.5 mg/kg) or morphine pharmacopuncture at Zusanli ST-36 (0.05 mg/kg): Comparison Between Experienced (EE) and Non-Experienced Evaluators (NEE).
DISCUSSION
The present study demonstrated that pharmacopuncture in Zusanli ST-36 with microdoses of morphine (equivalent to 10% of the intramuscular dose) provides a satisfactory analgesic effect in the postoperative management of dogs undergoing unilateral mastectomy, comparable to intramuscular morphine administration. The observed analgesic efficacy aligns with previous studies that have investigated the role of acupuncture techniques, such as pharmacopuncture and electroacupuncture, in modulating pain perception and enhancing perioperative analgesia (Cassu et al., 2014; Ariga et al., 2025).
ST-36 (Zusanli), a widely studied acupoint in Traditional Chinese Medicine, has been associated with analgesic effects, including increased pain thresholds and modulation of gastrointestinal motility (Marques et al., 2015). Its stimulation has been shown to enhance endogenous opioid release and activate neural pathways responsible for nociceptive modulation (Cassu et al., 2014; Fry et al., 2014; Silva et al., 2017). Additionally, research suggests that acupoint stimulation may involve the peripheral nervous system, including neurovascular bundles and perineural structures, facilitating signal conduction to the central nervous system, promoting both sedation and analgesia (Pons et al., 2017). The anatomical and functional proximity between connective tissue networks and acupuncture meridians further supports this hypothesis, with studies indicating that collagen-rich connective tissues may serve as electrical conductors in meridian signaling (Konofagou and Largevin, 2005; Luna et al., 2015).
Acupuncture has been extensively applied for pain management across various animal species, demonstrating its efficacy in alleviating both acute and chronic pain conditions (Magden, 2017; Fry et al., 2014; Hammad and Gadallah, 2023) Its therapeutic potential has also been associated with the prolonged effect of dexmedetomidine when administered via acupoint injection compared to conventional intramuscular administration in dogs (Pons et al., 2017). Furthermore, electroacupuncture has been reported to enhance pain thresholds in performance horses with chronic back pain (Rungsri et al., 2009), while its use in small animals, including cattle, cats, and dogs, has been associated with significant reductions in surgical pain (Xie and Sivula, 2016) Experimental investigations further support its analgesic properties, indicating its ability to modulate nociceptive processing and improve pain relief in controlled settings (Kim and Xie, 2009; Xie et al., 2009; Kim et al., 2013).
From a clinical perspective, acupuncture represents a viable alternative for pain management due to its ability to enhance physiological recovery rather than merely suppressing symptoms. Its minimally invasive nature, coupled with a favorable safety profile, makes it an appealing adjunctive therapy in veterinary practice (Hulea and Cristina, 2012; Magden, 2017). Reported adverse effects are infrequent and generally mild, with rare occurrences of minor complications such as localized hematoma, transient changes in energy levels, or accidental needle breakage (Hulea and Cristina, 2012).
Pharmacopuncture has emerged as a promising modality that integrates traditional acupoint stimulation with the localized administration of pharmacological agents, potentially enhancing and prolonging the therapeutic effects of the injected substance (Hammad and Gadallah, 2023). This technique has been successfully employed in veterinary medicine, with studies demonstrating its sedative effects in horses (Luna et al., 2008), and dogs (Cassu et al., 2014). Beyond sedation, pharmacopuncture has been investigated for its role in postoperative pain management. Research indicates that administering low-dose meloxicam (0.01mg/kg) at acupuncture points such as ST-36, SP-6, GB-34, and LIV-3 produces analgesic effects comparable to those achieved with higher doses given subcutaneously (0.1mg/kg) (Marques et al., 2015). Additionally, electroacupuncture at ST-36 and SP-6 has been shown to alleviate postoperative pain in dogs (Cassu et al., 2014) and reduce anesthetic requirements in cats undergoing ovariohysterectomy (Marques et al., 2015).
In the present study, pain assessment using the VAS and the CMPS-SF did not reveal statistically significant differences between the pharmacopuncture and intramuscular morphine groups. However, a trend toward lower pain scores in the pharmacopuncture group was observed, suggesting a potential clinical benefit. The need for rescue analgesia was noted as early as the first postoperative hour in both groups, persisting up to 8 hours postoperatively. This finding is consistent with reports indicating that acupuncture's analgesic effects can vary based on stimulation parameters and individual patient responses (Sousa et al., 2012; Hammad and Gadallah, 2023). Notably, studies have reported that electroacupuncture at ST-36 and SP-6 resulted in sufficient analgesia for abdominal surgery in 25%-89% of treated animals (Sousa et al., 2012).
The use of lower doses of morphine in the pharmacopuncture group is consistent with findings from previous studies. Luna et al. (2008) demonstrated that the injection of a microdose of acepromazine (1/10 of the conventional dose) into the Yin Tang acupoint in dogs reduced the required dose of thiopental for anesthetic induction by 32%, compared to a 51% reduction in animals receiving the full dose subcutaneously. These findings suggest that acupoint administration may enhance the pharmacodynamic effects of certain drugs, improving clinical outcomes even at lower doses. This dose-sparing effect may be particularly advantageous with opioids such as morphine, which are associated with dose-dependent adverse effects, including vomiting, respiratory depression, urinary retention, excitement or dysphoria, and histamine release (Paul et al., 2021). Therefore, achieving comparable analgesic efficacy with significantly lower doses such as those used in pharmacopuncture may improve patient safety and comfort in the perioperative setting.
The analgesic mechanisms underlying acupuncture and pharmacopuncture are still not fully elucidated. However, it is widely accepted that endogenous opioids, including endorphins, enkephalins, and dynorphins, play a significant role in acupuncture-mediated pain relief through their interaction with mu, delta, and kappa opioid receptors (Fry et al., 2014; Luna et al., 2015). Additionally, neurotransmitters such as serotonin, dopamine, acetylcholine, norepinephrine, and gamma-aminobutyric acid have been implicated in acupuncture’s analgesic effects (Chen et al., 2009). The increased blood flow and vasodilation in the needled area have also been suggested as contributing factors to acupuncture-induced pain modulation (Alimi et al., 2020).
The correlation analysis revealed a strong agreement between experienced and non-experienced evaluators for both VAS and CMPS-SF. These findings suggest that the structured nature of the CMPS-SF, which organizes behavioral parameters into defined categories, including interaction with the environment, response to palpation, posture, and vocalization may have facilitated the training and adaptation of the non-experienced evaluator. As a result, over the course of the study, the non-experienced evaluator developed greater sensitivity to baseline assessments, leading to more precise pain evaluations using VAS.
This study presents some limitations. One of them is the relatively small sample size, which was determined with an alpha level of 5% (two-sided), beta of 20% (80% power), and an assumed clinically significant reduction in postoperative rescue analgesia of 20% based on an expected in CMPS-SF pain scores between groups. However, the actual intergroup differences observed were smaller, potentially affecting the statistical power of the analysis. Another limitation is the absence of a sham acupuncture control group. Neuroimaging studies have shown that stimulating non-acupuncture points can still trigger analgesic effects by activating cortical and subcortical regions associated with nociception (Schockert et al., 2010). Given these findings and ethical considerations, a placebo acupuncture group was not included in this study.
CONCLUSIONS
In conclusion, our findings support the hypothesis that pharmacopuncture at ST-36 with microdoses of morphine (equivalent to 10% of the intramuscular dose) provides complementary postoperative analgesia comparable to conventional intramuscular administration in dogs undergoing unilateral mastectomy. Although further research is needed to optimize stimulation protocols and elucidate the precise neurophysiological mechanisms, pharmacopuncture represents a promising adjuvant technique for pain management in veterinary practice.
ACKNOWLEDGMENTS
The authors would like to express their gratitude to Professors Drs. Luara da Rosa, Vanessa Sasso Padilha and Ademir Cassiano da Rosa for their invaluable theoretical and practical support throughout the study. We also extend our appreciation to Veterinarians Marilia Gabrieli Luciani and Amarildo Oliveira Lyra de Souza for their dedicated assistance in the postoperative care and follow-up of the patients. This study was financially supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil.
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Data-available-upon-request - the research data are available upon request
