A nationwide retrospective cohort study of the association between acupuncture exposure and clinical outcomes of idiopathic Parkinson’s disease using health insurance claim data in South Korea

Abstract

Background

Idiopathic Parkinson’s disease (IPD) has been associated with increased global mortality. While acupuncture has been reported to slow IPD progression, its effect on mortality remains unclear. This study investigated the association between acupuncture exposure and mortality, causes of death, and prognosis in patients with IPD.

Methods

Using customized cohort data from the National Health Insurance Service (NHIS), we analyzed patients newly diagnosed with IPD without disabilities between 2012 and 2016. Patients were classified into an acupuncture group (≥six sessions within 1 year of diagnosis) and a non-acupuncture group. Propensity score matching (PSM) was applied, and Cox proportional hazards models were used for survival analysis. During a 6-year follow-up, hazard ratios (HRs) were estimated for overall and cause-specific mortality, emergency room visits, fractures, and the first deep brain stimulation (DBS) procedure, using the non-acupuncture group as the reference.

Results

After PSM, 6394 patients were included in each group. The HR for mortality in the acupuncture group was 0.887 (95 % CI: 0.813−0.967), indicating a significantly lower mortality risk. Deaths due to neoplasms and digestive diseases were also lower in the acupuncture group. No significant differences were observed between groups in fracture risk, emergency room visits, or DBS procedures.

Conclusions

Acupuncture exposure was associated with a reduced mortality rate in patients with IPD. These findings suggest potential benefits of integrating acupuncture into IPD management, though further long-term randomized controlled trials are needed to confirm these results.

1. Introduction

Idiopathic Parkinson’s disease (IPD) is a progressive neurodegenerative disorder characterized by motor symptoms such as tremor, rigidity, and bradykinesia, as well as non-motor symptoms including pain, sleep disturbances, orthostatic hypotension, and depression.^1,2 It is caused by the degeneration of dopaminergic neurons in the substantia nigra of the midbrain and is attributed to various genetic and environmental factors.^3,4 With an improving life expectancy and rising older population, the incidence of IPD has also increased. Recent epidemiological studies have reported that the prevalence of Parkinson’s disease varies across countries, ranging from approximately 0.108–0.212 % in the United States,⁵ 0.22–1.70 % in the United Kingdom.⁶ In particular, the prevalence increases among the elderly, and in China, the prevalence rate for individuals aged 65 and older is reported to be approximately 1.6 %.⁷ A nationwide study using Korean health insurance data reported that the prevalence of Parkinson’s disease increased from 186.3 per 100,000 persons in 2016 to 233.7 per 100,000 persons in 2022.⁸ The majority of patients were aged 65 years or older, with the highest prevalence observed in individuals aged over 70, particularly among women aged over 80. The economic burden of Parkinson’s disease (PD) in the United States has reached approximately $51.9 billion and is projected to escalate to approximately $79 billion by 2037.⁹ As the disease progresses, the risks of falls, aspiration pneumonia, and pressure ulcers increase, potentially leading to severe functional disabilities or death.10, 11, 12 Patients with IPD have been found to have a 1.62-times higher risk of death than those without IPD, with an especially higher risk of death from circulatory system diseases.¹³

Although dopaminergic drugs developed in the 1960s are considered the standard pharmacological treatment, they have limitations due to side effects such as indigestion, dizziness, headaches, and constipation, which can reduce the quality of life. Additionally, dyskinesia may occur due to the on-off phenomenon.^14,15 Consequently, there is a growing demand for the development of alternative sustainable interventions and treatments to manage symptoms effectively. In East Asia, various East Asian Traditional Medicine interventions, such as herbal medicine, acupuncture, and qi-gong, are frequently used in the management of Parkinson’s disease.¹⁶ Notably, acupuncture is widely utilized in clinical practice, and related research is actively being conducted.¹⁷ Experimental studies have reported that acupuncture treatments at LR3 (Taichong), GB34 (Yanglingquan), and ST36 (Zusanli) regulate the nigrostriatal dopaminergic system, providing neuroprotective effects. Additionally, these treatments are known to modulate gut microbiota imbalances, thereby helping restore balance to the dopaminergic circuit and potentially slowing the progression of the disease.18, 19, 20 Clinical studies have also shown that acupuncture is effective in reducing the incidence of IPD by addressing prodromal symptoms, such as sleep disturbances and depression.^21,22 Furthermore, acupuncture better improves motor symptoms than standard standalone treatments, with standard treatments combined with bee venom acupuncture or electroacupuncture reporting enhanced efficacies.²³ However, despite the numerous clinical studies conducted on acupuncture, few randomized controlled trials (RCTs) examine its impact on mortality and prognosis in patients with IPD. Investigating this topic requires long-term follow-up. Additionally, conducting such RCTs is challenging due to various practical constraints, including financial limitations. Therefore, it is essential to accumulate evidence on the long-term prognosis of acupuncture in PD through observational studies utilizing real-world data, such as claims databases.

In South Korea, acupuncture treatment is covered by the National Health Insurance (NHI), and its claims data are digitized, enabling cohort studies on the impact of acupuncture on the prognosis of specific disease groups at the national level.²⁴ Therefore, this study aimed to observe the long-term effects of acupuncture in patients with IPD by analyzing overall and disease-specific mortality rates, the incidence of fractures, the number of patients who visited the emergency room, and first deep brain stimulation (DBS) session. By leveraging data from the NHI claims database, this study aimed to build evidence on the clinical association between acupuncture exposure and the prognoses of patients with IPD, providing insights that are challenging to obtain without resource-intensive long-term RCTs. In this study, propensity score matching (PSM) was applied to match patients with IPD in the acupuncture-exposed and non-exposed groups. Survival analysis was performed using the Cox proportional hazards model to estimate hazard ratios (HRs) for differences in various clinical indicators within a 6-year follow-up period based on acupuncture exposure within 1 year after IPD diagnosis.

2. Methods

The study’s design was based on the "Study Design Diagram for Acupuncture Research Using RWD with a Cohort Design" proposed by Lee et al. and is presented in Fig. 1.²⁵

Fig. 1.

Study design diagram.

ATx, Acupuncture treatment; CCI, Charlson Comorbidity Index.

* The disability grade is assigned only to individuals who have been diagnosed with a disability in accordance with Article 32 of the Disability Welfare Act.

** Full list and codes of acupuncture treatments are in the methods section.

† The residential area has been classified into metropolitan, urban, and rural categories.

‡ Pre-specified comorbidities include hypertension, diabetes mellitus, dyslipidemia, cardiovascular disease, renal failure, stroke, chronic obstructive pulmonary disease, and cancer.

¥ Censored at earliest of outcome, death, dropout, or end of study period.

2.1. Data sources

South Korea has 51,417,000 NHI enrollees, as all citizens are covered under the NHI system. The NHI covers medical service costs across a wide range of areas, including disease prevention, diagnosis, treatment, rehabilitation, injury, childbirth, and death, thereby improving public health and promoting social security. This retrospective cohort study used customized cohort data provided by the National Health Insurance Service (NHIS) (Study Management Number: REQ202300576–002). The NHIS database contains comprehensive patient information including diagnostic codes, healthcare utilization, prescriptions, vital signs, disability grades, sex, age, and socioeconomic factors, such as health insurance premium brackets.²⁶ This study was exempted from review by the Institutional Review Board (IRB) of Kyung Hee University Hospital at Gangdong (Approval Number: KHNMCOH 2023–01–004) because the data were anonymized.

2.2. Study population

The study population included patients with IPD (ICD Code G20), aged ≥19 years, newly diagnosed between January 1, 2012, and December 31, 2016. Only non-disabled individuals—without a disability grade at the time of initial diagnosis—were included. Patients with a diagnosis of IPD (G20) during the 2 years prior (January 1, 2010, to December 31, 2011), those who received acupuncture treatment within 6 months prior (washout period), or those who were diagnosed with dementia or died within 1 year of their initial IPD diagnosis before enrollment were excluded from the study (Fig. 1).

2.3. Definition of acupuncture-exposed and non-exposed groups

Among the study participants, those who received acupuncture treatment ≥six times within 1 year of their diagnosis were classified into the acupuncture group, while those who did not receive any acupuncture treatment within 1 year of their diagnosis were classified into the non-acupuncture group. This threshold was based on previous retrospective cohort studies using national health insurance data, where the same criterion (≥6 sessions) has been widely applied in evaluating the therapeutic effects of acupuncture.^21,27,28 Patients who received acupuncture one to five times within the first year after IPD diagnosis were excluded from this study. Acupuncture treatments were identified using the following codes: 40,011 (acupuncture at one acupoint), 40,012 (acupuncture at ≥ 2 acupoints), 40,030 (ocular acupuncture), 40,040 (intranasal acupuncture), 40,050 (intra-abdominal acupuncture), 40,060 (intra-articular acupuncture), 40,070 (intervertebral acupuncture), 40,080 (moxibustion acupuncture), and 40,091 (electroacupuncture).²⁵

2.4. Outcomes

The exposure window for acupuncture treatment was set as the 1 year following the cohort entry date (the date of IPD diagnosis). The index date was defined as 1 year after the diagnosis, and the participants were followed up for up to 6 years from the index date to observe the outcome measures (Fig. 1).

The primary endpoint was all-cause mortality. The specific causes of death were classified based on the Korean Standard Classification of Diseases, in combination with data from Statistics Korea. The causes were categorized as follows: infections (A00–B99); neoplasms (C00–D49); diseases of the blood and blood-forming organs and immune mechanisms (D50–D89); endocrine, nutritional, and metabolic diseases (E00–E88); mental and behavioral disorders (F00–F99); diseases of the nervous system (G00–G99); diseases of the circulatory system (I00–I99); diseases of the respiratory system (J00–J98); diseases of the digestive system (K00–K92); diseases of the musculoskeletal system and connective tissue (M00–M99); diseases of the genitourinary system (N00–N98); symptoms, signs, and abnormal clinical and laboratory findings not elsewhere classified (R00–R99); injuries, poisoning, and other consequences of external causes (S00–T98); and other causes (H00–H59, L00–L99, O00–O9A, Q00–Q99, and Z00–Z99).²⁹ The HR for the risk of death for each cause was calculated for the acupuncture group, using the non-acupuncture group as the reference.

The secondary endpoints included the incidence of fractures, the first emergency room visit, and the first DBS event in patients with IPD. DBS is performed when motor symptoms are not controlled with medication and when there is a response to levodopa but with severe side effects. Since this indicates that the symptoms have worsened, we aimed to investigate whether exposure to acupuncture treatment is related to the progression rate of symptoms.³⁰ They was identified based on outpatient visits (two or more visits) or hospitalization (one or more admissions) for fractures (vertebral fractures S22, S22.1, S32, M48.4, M48.5; other fractures S42.0, S42.2, S42.3, S52.5, S82.3, S82.5, S82.6; hip fractures S72.0, S72.1), with follow-ups conducted from the index date until the end of the study period.¹¹ The emergency room visit from the index date was assessed. DBS was identified by checking the records for the procedure codes S0471, S0477, S0478, and S0472.³¹

2.5. Covariates

The health indicators used for the propensity score of the study participants were as follows: age at initial IPD diagnosis (≤59, 60−79, ≥80 years), sex, health insurance premium (lower 0 − 6, middle 7 − 13, upper 14−20), residential area (metropolitan, urban, rural area), and comorbidities within the past year, including hypertension, diabetes, dyslipidemia, cardiovascular disease, renal failure, stroke, chronic obstructive pulmonary disease, and cancer, as assessed by the Charlson Comorbidity Index (CCI score).³² Hypertension (I10–I13, I15), diabetes (E10–E14), dyslipidemia (E78), cardiovascular disease (I05–I09, I20–I27, I30–I52), renal failure (N17–N19), stroke (I60–I69), chronic obstructive pulmonary disease (J41–J44), and cancer (C00–C26, C30–C34, C37–C41, C43, C45–C49, C50–C58, C60–C85, C88, C90–C97) were confirmed based on occurrences from 1 year prior to the enrollment date. These factors were then used for 1:1 matching between the acupuncture and non-acupuncture groups based on the propensity score of the non-acupuncture group.^25,33

2.6. Statistical analysis

Continuous variables are reported as means ± standard deviations, while categorical variables are reported as frequencies and percentages (%). PSM was used to adjust potential bias in baseline characteristics. The greedy nearest-neighbor matching method was used, with the caliper set to 0.01. The propensity score was calculated using a logistic regression model that included age, sex, income, year of diagnosis, residence, CCI, and comorbidities as covariates. The standardized mean differences between the two groups for the covariates used in the matching were tested for significance at a threshold of p < 0.01.

The total number of events and total person-years (PY) are presented for all-cause and disease-specific mortality and other secondary outcome variables, and the event rate is expressed as the incidence rate (IR) per 1000 PY. The crude hazard ratios (cHRs) and adjusted hazard ratios (aHRs), with 95 % confidence intervals (CIs), are provided for all-cause mortality, disease-specific mortality, and other secondary outcome variables. Adjustments were made for age, sex, health insurance premium, year of diagnosis, residence, CCI, and comorbidities.

HRs were calculated using a Cox proportional hazards model. Visually, Kaplan−Meier curves were used to show the cumulative incidence of all-cause mortality, emergency visits, fractures, and DBS implementation to test for differences between the acupuncture-exposed and non-acupuncture-exposed groups. The data analysis for this study was conducted using SAS software (version 9.4, Copyright © 2024 SAS Institute Inc., Cary, NC, USA), and statistical significance was defined as a p < 0.05.

3. Results

3.1. Participants

Between 2012 and 2016, 199,462 individuals were newly diagnosed with PD. Among them, 47,549 had a disability rating, and 62,747 had received acupuncture treatment before 6 months of their first PD diagnosis. After excluding 410 patients with missing demographic information and 45,852 patients diagnosed with dementia or those who passed away within 1 year of the enrollment date, the total number of patients was 41,337. Among these, 7091 patients who received between one and five acupuncture sessions within the first year of IPD diagnosis were also excluded, leaving 6400 patients in the acupuncture group and 27,846 in the non-acupuncture group. PSM was performed using age, health insurance premium bracket, year of diagnosis, residence, CCI, and comorbidities as covariates. After a 1:1 matching, 6394 patients were enrolled in each group (Fig. 2).

Fig. 2.

Screening flow chart of patients with Parkinson’s disease from the National Health Insurance Service System (NHISS).

#1–5, received acupuncture treatment one to five times; A-Tx, Acupuncture treatment; CCI, Charlson Comorbidity Index; Rx, Recipe take.

3.2. Baseline characteristics

The characteristics of the included participants before and after PSM between the acupuncture and non-acupuncture groups are presented in Table 1. Before PSM, the acupuncture group was older than the non-acupuncture group and had a higher proportion of females. The proportion of patients residing in urban areas was lower. A higher proportion of patients in the acupuncture group had a CCI score ≥3. The acupuncture group also had significantly higher rates of comorbidities, including hypertension, diabetes, hyperlipidemia, cardiovascular disease, stroke, chronic obstructive pulmonary disease, and cancer. No significant differences remained in any of the covariates after 1:1 matching of the acupuncture and non-acupuncture groups (Table 1).

Table 1.

Baseline characteristics of acupuncture-exposed and non-exposed patients with Parkinson’s disease before and after propensity score matching.

Variable		Before PSM			After PSM
		Acupuncture (N = 6400)	Non-acupuncture (N = 27,846)	SMD	Acupuncture (N = 6394)	Non-acupuncture (N = 6394)	SMD
Age, mean (SD)		65.69 ± 13.22	60.42 ± 17.94	0.3346	65.68 ± 13.22	65.99 ± 14.12	0.023
Age, n (%)	≤59	1738 (27.16)	11,183 (40.16)	0.2873	1738 (27.18)	1712 (26.78)	0
	60−79	3938 (61.53)	13,557 (48.69)		3932 (61.50)	3913 (61.20)
	≥80	724 (11.31)	3106 (11.15)		724 (11.32)	769 (12.03)
Sex, n (%)	Male	2596 (40.56)	14,199 (50.99)	0.2105	2596 (40.60)	2613 (40.87)	0.005
	Female	3804 (59.44)	13,647 (49.01)		3798 (59.40)	3781 (59.13)
Income, n (%)	Low	1748 (27.31)	7974 (28.64)	0.0611	1748 (27.34)	1746 (27.31)	0
	Middle	1562 (24.41)	6870 (24.67)		1561 (24.41)	1560 (24.40)
	High	3090 (48.28)	13,002 (46.69)		3085 (48.25)	3088 (48.30)
Diagnosis year, n (%)	2012	1323 (20.67)	5034 (18.08)	0.0994	1317 (20.60)	1265 (19.78)	0.0442
	2013	1263 (19.73)	5296 (19.02)		1263 (19.75)	1228 (19.21)
	2014	1168 (18.25)	5240 (18.82)		1168 (18.27)	1168 (18.27)
	2015	1292 (20.19)	6501 (23.35)		1292 (20.21)	1314 (20.55)
	2016	1354 (21.16)	5775 (20.74)		1354 (21.18)	1419 (22.19)
Residential area, n (%)	Metropolitan	2934 (45.84)	12,947 (46.50)	0.057	2934 (45.89)	2961 (46.31)	0
	Urban	1285 (20.08)	4994 (17.93)		1279 (20.00)	1292 (20.21)
	Rural	2181 (34.08)	9905 (35.57)		2181 (34.11)	2141 (33.48)
CCI, n (%)	0	169 (2.64)	1518 (5.45)	0.276	169 (2.64)	170 (2.66)	0
	1	335 (5.23)	2789 (10.02)		335 (5.24)	321 (5.02)
	2	540 (8.44)	3253 (11.68)		540 (8.45)	533 (8.34)
	≥3	5356 (83.69)	20,286 (72.85)		5350 (83.67)	5370 (83.98)
Comorbidities, n (%)	HTN	4368 (68.25)	16,767 (60.21)	0.1683	4362 (68.22)	4351 (68.05)	0.0037
	DM	3632 (56.75)	13,936 (50.05)	0.1347	3630 (56.77)	3689 (57.69)	0.019
	Dyslipidemia	4823 (75.36)	18,735 (67.28)	0.1793	4817 (75.34)	4841 (75.71)	0.009
	CVD	3358 (52.47)	12,589 (45.21)	0.1456	3353 (52.44)	3341 (52.25)	0.0038
	Renal failure	356 (5.56)	1593 (5.72)	0.0069	356 (5.57)	345 (5.40)	0.0076
	Stroke	2522 (39.41)	9129 (32.78)	0.1382	2520 (39.41)	2519 (39.40)	0.0003
	COPD	3135 (48.98)	11,520 (41.37)	0.1534	3129 (48.94)	3112 (48.67)	0.0053
	Cancer	2791 (43.61)	8548 (30.70)	0.2696	2785 (43.56)	2749 (42.99)	0.0114

Acupuncture, patients with acupuncture exposure ≥6 times within 12 months post-diagnosis; Non-acupuncture, patients not exposed to acupuncture within the 12 months after diagnosis;.

CCI, Charlson Comorbidity Index; COPD, chronic obstructive pulmonary disease; CVD, cardiovascular disease; DM, diabetes mellitus; HTN, hypertension; PSM, propensity score matching; SD, standard deviation; SMD, standardized mean difference.

3.3. Primary outcome: mortality rates

3.3.1. All-cause mortality

The mortality rate for all causes tended to be lower in the acupuncture group than in the non-acupuncture group. The mortality rate was 27.0/1000 PY in the acupuncture group and 31.9/1000 PY in the non-acupuncture group. The cHR for all-cause mortality was 0.842 (95 % CI: 0.773−0.918). After adjustment, the HR for mortality was 0.887 (95 % CI: 0.813−0.967) in the acupuncture group compared to the non-acupuncture group (Table 2). The Kaplan−Meier curves for all-cause mortality are presented in Fig. 3.

Table 2.

Crude and adjusted hazard ratios and 95 % confidence intervals for mortality rates.

	N	Events	IR per 1000 PY	Crude		Adjusted†
				HR (95 % CI)	p-value	HR (95 % CI)	p-value
All causes of death
Non-acup	6394	1118	31.9	1 (Ref.)		1 (Ref.)
Acup	6394	960	27.0	0.842 (0.773−0.918)	<0.0001*	0.887 (0.813−0.967)	0.0063*
Infectious(A00–B99)
Non-acup	6394	31	0.9	1 (Ref.)		1 (Ref.)
Acup	6394	28	0.8	0.885 (0.531−1.476)	0.6401	0.936 (0.561−1.562)	0.7993
Neoplasm(C00–D48)
Non-acup	6394	234	6.7	1 (Ref.)		1 (Ref.)
Acup	6394	174	4.9	0.731 (0.6 − 0.889)	0.0017*	0.764 (0.628−0.93)	0.0073*
Hematologicz and immune (D50–D89)
Non-acup	6394	1	0.0	1 (Ref.)		1 (Ref.)
Acup	6394	4	0.1	3.943 (0.441−35.28)	0.2198	4.008(0.445−36.083)	0.2157
Endocrine and metabolic(E00–E88)
Non-acup	6394	49	1.4	1 (Ref.)		1 (Ref.)
Acup	6394	34	1.0	0.68 (0.439−1.053)	0.0836	0.724 (0.467−1.122)	0.1483
Mental(F00–F99)
Non-acup	6394	16	0.5	1 (Ref.)		1 (Ref.)
Acup	6394	8	0.2	0.49 (0.21−1.144)	0.0991	0.52 (0.222−1.219)	0.1326
Nervous(G00–G99)
Non-acup	6394	163	4.7	1 (Ref.)		1 (Ref.)
Acup	6394	191	5.4	1.147 (0.93−1.413)	0.1994	1.201 (0.974−1.481)	0.0864
Circulatory(I00–I99)
Non-acup	6394	208	5.9	1 (Ref.)		1 (Ref.)
Acup	6394	172	4.8	0.812 (0.664−0.994)	0.0436*	0.857 (0.7 − 1.05)	0.136
Respiratory(J00–J98)
Non-acup	6394	137	3.9	1 (Ref.)		1 (Ref.)
Acup	6394	131	3.7	0.936 (0.737−1.189)	0.5887	1.01 (0.795−1.285)	0.9324
Digestive(K00–K92)
Non-acup	6394	41	1.2	1 (Ref.)		1 (Ref.)
Acup	6394	24	0.7	0.575 (0.347−0.952)	0.0313*	0.591 (0.357−0.979)	0.0411*
Musculoskeletal(M00–M99)
Non-acup	6394	2	0.1	1 (Ref.)		1 (Ref.)
Acup	6394	2	0.1	0.976 (0.137−6.928)	0.9805	1.048 (0.138−7.975)	0.964
Genitourinary(N00–N98)
Non-acup	6394	27	0.8	1 (Ref.)		1 (Ref.)
Acup	6394	24	0.7	0.872 (0.503−1.511)	0.6251	0.923 (0.531−1.602)	0.7746
Unclassified(R00–R99)
Non-acup	6394	117	3.3	1 (Ref.)		1 (Ref.)
Acup	6394	77	2.2	0.644 (0.483−0.859)	0.0027*	0.706 (0.529−0.942)	0.018*
External(S00–T98)
Non-acup	6394	74	2.1	1 (Ref.)		1 (Ref.)
Acup	6394	82	2.3	1.09 (0.796−1.492)	0.591	1.105 (0.806−1.513)	0.5353
Other
Non-acup	6394	18	0.5	1 (Ref.)		1 (Ref.)
Acup	6394	9	0.3	0.491(0.221−1.093)	0.0815	0.491 (0.22−1.095)	0.0823

Acup, patients with acupuncture exposure ≥six times within 12 months post-diagnosis; Non-acup, patients not exposed to acupuncture within the 12 months after diagnosis;.

CI, confidence intervals; CCI, Charlson Comorbidity Index; HR, hazard ratio; IR, incidence rate; PY, person-years; Ref., reference.

^⁎Statistically significant (p < 0.05).

^†Cox proportional hazards model was used. Adjusted for age, sex, income, diagnosis year, residential area, CCI score, and comorbidities.

Fig. 3.

Kaplan-Meier survival analysis of all-cause mortality: Acupuncture vs non-acupuncture group.

Statistical analysis for the Kaplan−Meier curve was performed using the log-rank test. Kaplan–Meier curves demonstrate a significant difference in survival probability for all-cause mortality between the acupuncture and non-acupuncture treatment groups. (p < 0.0001) (Red: Acupuncture [patients with acupuncture exposure ≥six times within 12 months post-diagnosis], Blue: Non-acupuncture [patients not exposed to acupuncture within 12 months after diagnosis]).

3.3.2. Disease-specific mortality

In both groups, the mortality rate due to neoplasms (C00−D48), diseases of the nervous system (G00−G99), and diseases of the circulatory system (I00−I99) accounted for a large proportion of deaths. The mortality due to neoplasms (C00−D48), diseases of the digestive system (K00−K92), and other specified symptoms, signs, and abnormal clinical and laboratory findings (R00−R99) was significantly lower in the acupuncture group than in the non-acupuncture group. The aHR for mortality due to neoplasms was 0.764 (95 % CI: 0.628−0.93), digestive system disorders was 0.591 (95 % CI: 0.357−0.979), and other unspecified symptoms and signs in the acupuncture group was 0.706 (95 % CI: 0.529−0.942). There were no significant differences in the other causes of death between the acupuncture and non-acupuncture groups (Table 2).

3.4. Secondary outcomes: incidences of fracture, emergency care visits, and DBS

There was no significant statistical difference in the incidence of fractures between the two groups (aHR = 1.059, 95 % CI: 0.977−1.149). The number of patients who visited the emergency room was slightly lower in the acupuncture group; however, the difference was not statistically significant (aHR = 0.994, 95 % CI: 0.938–1.054). This minimal difference was consistent across both the tabulated data and the survival curve analysis. There was no significant difference between the two groups in the rate of DBS performance (aHR = 1.128, 95 % CI: 0.563−2.262). The Kaplan−Meier curves for these outcomes are presented in Fig. 4 (Table 3).

Fig. 4.

Kaplan-Meier survival analysis of fracture, emergency care visit, and deep brain stimulation: Acupuncture vs non-acupuncture group.

Statistical analysis for the Kaplan−Meier curve was performed using the log-rank test. Kaplan–Meier curves show survival probability in both the acupuncture and non-acupuncture groups for (A) fracture (p = 0.1301), (B) emergency care visit (p = 0.3927), and (C) deep brain stimulation (p = 0.8965), with no significant difference between the two groups. (Red: acupuncture [patients with acupuncture exposure ≥six times within 12 months post-diagnosis], Blue: Non-acupuncture [patients not exposed to acupuncture within 12 months after diagnosis]).

Table 3.

Crude and adjusted hazard ratios and 95 % confidence intervals for fracture, emergency care visits, and deep brain stimulation.

	N	Events	IR /1000 PY	Crude		Adjusted†
				HR (95 % CI)	p-value	HR (95 % CI)	p-value
Fracture
Non-acup	6394	1154	32.4	1 (Ref.)		1 (Ref.)
Acup	6394	1204	35.1	1.036 (0.956−1.123)	0.3919	1.059 (0.977−1.149)	0.1629
Emergency
Non-acup	6394	2266	74.7	1 (Ref.)		1 (Ref.)
Acup	6394	2240	73.2	0.978 (0.923−1.037)	0.4571	0.994 (0.938−1.054)	0.843
Deep brain stimulation
Non-acup	6394	15	0.4	1 (Ref.)		1 (Ref.)
Acup	6394	17	0.5	1.111 (0.555−2.225)	0.7658	1.128 (0.563−2.262)	0.7337

Acup, patients with acupuncture exposure ≥six times within 12 months post-diagnosis; Non-acup, patients not exposed to acupuncture within the 12 months after diagnosis;.

CI, confidence intervals; CCI, Charlson Comorbidity Index; HR, hazard ratio; IR, incidence rate; PY, person-years; Ref., reference.

*Statistically significant (p < 0.05).

†Cox proportional hazards model was used. Adjusted for age, sex, income, diagnosis year, residential area, CCI score, and comorbidities.

4. Discussion

4.1. Summary of findings

This study investigated the association between acupuncture exposure in patients with IPD and long-term outcomes, which has not been explored in the previous literature. The study examined whether exposure to acupuncture treatment after the diagnosis of IPD influences long-term clinical indicators, such as mortality, and revealed a HR of 0.88 in the acupuncture-exposed group compared to the non-acupuncture-exposed group.

4.2. Acupuncture exposure on all-cause and disease-specific mortality

Numerous studies have analyzed factors affecting mortality, highlighting that compared to individuals without IPD, the mortality rate is twice as high among patients with IPD.²⁹ Diverse factors, such as male sex, motor symptoms above Hoehn and Yahr stage 3, absence of tremor at the onset of IPD, psychiatric symptoms such as dementia and delirium, and the presence of bilateral rather than unilateral motor symptoms at onset, contribute to an increased mortality rate.^34,35 According to an Australian cohort study, an older age at onset and pesticide exposure were found to influence mortality.³⁶ Additionally, coffee consumption and moderate alcohol intake were associated with a reduced mortality rate.³⁷ For patients with IPD, early DBS reportedly results in the worsening of both motor and non-motor symptoms as the disease progresses. Still, researchers debate whether DBS is linked to an increase or decrease in mortality.^36,38

No cohort studies or RCTs have examined mortality as an endpoint in acupuncture treatment for IPD. In RCTs involving acupuncture for patients with IPD, the focus has primarily been on motor symptoms, non-motor symptoms, or the quality of life rather than survival. The follow-up periods for these studies ranged from a minimum of 2 weeks to a maximum of 36 weeks.39, 40, 41 However, these studies had short follow-up durations, and mortality was not considered a feasible endpoint for assessment, implying a lack of RCTs specifically focused on mortality in this context. Through Taiwan’s National Health Insurance Research Database, it was found that patients with PD who used Traditional Chinese Herbal Medicine (TCHM) had a relatively lower incidence of stroke than those who did not use TCHM.⁴² However, their study focused on herbal medicine rather than acupuncture treatment. In South Korea, a retrospective cohort study on acupuncture exposure using health insurance claims data has also been published.⁴³ However, their study used a sample cohort rather than customized data, had a relatively small sample size of 300 patients per group, and followed up patients for only 4 years, which is a relatively short period. As mentioned above, there are very few real-world data-based studies that address the relationship between acupuncture exposure and mortality in patients with PD.⁴²

The mortality rate among patients with IPD was twice as high compared to individuals without PD, with leading causes of death including neurological diseases, cardiovascular diseases, pneumonia, and infections.²⁹ The reduced mobility due to tremors, postural imbalance, and rigidity likely leads to poor circulation and decreased gastrointestinal motility, resulting in bowel obstructions and impaired swallowing, which in turn lead to recurrent aspiration pneumonia.¹² In our study, the acupuncture-exposed group exhibited a lower mortality rate than the non-exposed group following an IPD diagnosis. This may be attributable to various mechanisms associated with acupuncture in the management of IPD. Many reports suggest that acupuncture helps improve motor symptoms in patients with IPD, with experimental evidence that supports this improvement being well-documented. IPD is characterized by a lack of dopamine, leading to motor symptoms. Acupuncture treatment at GV 20 (Baihui) and GV 14 (Dazhui) promotes the production of vesicular glutamate transporter 1 (VGluT1), activates the neuron survival pathway, regulates neurotransmitters and receptors, including enkephalin and GAD67 genes, and stimulates the production of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor, which support dopamine neurons. This process reduces dopaminergic neuron apoptosis. Additionally, acupuncture treatment at GB34 (Yanglinquan) and GB39 (Xuanzhong) reportedly prevents the loss of dopamine neurons by inhibiting tyrosine hydroxylase-positive neuronal fiber reduction.⁴⁴ Stimulation of GB34 also activates the hypothalamus and hippocampus to secrete melanin-concentrating hormone, which improves motor functions not controlled by levodopa and enhances memory.45, 46, 47 Additionally, improvements in motor symptoms have been closely linked to a reduction in overall mortality and fracture incidence rate.⁴⁸

In our study, significant differences in the causes of death were observed, including digestive system diseases, neoplasms, and other classified symptoms and abnormal clinical findings. The reason for the reduction in mortality due to digestive system diseases following acupuncture exposure has not been clearly identified, but several possible explanations can be proposed. Patients with PD frequently report a decline in their quality of life due to gastrointestinal disorders. These include gastrointestinal dysfunction, weight loss, gastroparesis, small intestinal bacterial overgrowth syndrome, and constipation.¹ The autonomic nervous system regulates the gastrointestinal system, and as PD progresses, autonomic nerve fibers degenerate, synapses are lost, and nerve damage occurs, resulting in a decline in function. The accumulation of α-synuclein further exacerbates this impairment.⁴⁹ Therefore, the difference in mortality due to gastrointestinal diseases between the two groups may be attributed to the potential of acupuncture to regulate the autonomic nervous system and modulate gut microbiota, which could improve gastrointestinal function.^50,19 However, these hypotheses need to be validated through further studies. Similarly, the reason for the reduced mortality due to neoplastic diseases following acupuncture exposure remains unclear, but various potential factors can be considered. Patients with IPD have a lower risk of cancers, such as lung, urogenital, gastrointestinal, and hematologic cancers, while the risk of melanoma and brain cancer is increased.⁵¹ It is hypothesized that α-synuclein may play a role in the progression of melanoma and brain cancer and may help suppress the accumulation of α-synuclein. This potential effect may be reflected in the outcomes of this study. A Taiwanese epidemiological study observed that combined traditional Chinese medicine (TCM) treatment improved the quality of life and reduced mortality in patients with breast cancer. However, similar studies assessing the benefits of TCM on other cancers are scarce.⁵² Nonetheless, their study involved the combined use of acupuncture and herbal medicine; thus, it is difficult to determine the independent effect of acupuncture treatment. Further research is needed to investigate the effects and mechanism of acupuncture exposure on mortality from neoplasms.

4.3. Acupuncture exposure and complications and prognosis of IPD

In our study, there were no significant differences in secondary outcomes related to PD complications and prognosis, such as emergency room visits, DBS, and fractures. In previous studies, analysis of cohorts involving older adults showed that patients with PD who received more acupuncture treatments had shorter hospital stays for pneumonia and sepsis.⁴³ In Taiwan, patients who received TCM, including acupuncture, had a lower risk of fractures.⁵³ Complications in IPD tend to develop quickly and worsen; therefore, retrospective cohort study designs may not be suitable for evaluating the preventive effects of related diseases and complications. The diagnostic codes in claims data are sometimes used for billing purposes related to specific medications, which limit their reliability in assessing complications or adverse effects. Therefore, when using claims data for cohort studies, evaluating complications or adverse events may be challenging unless the outcome is clearly objective, such as death, hospitalization, or specific procedures. Additionally, although the PSM technique was used, disease severity and stage, as assessed by the Unified Parkinson’s Disease Rating Scale (UPDRS) and Hoehn and Yahr stages, which can influence secondary outcomes such as adverse effects and complications, could not be acquired from the claims data. This may have contributed to the lack of differences in secondary outcomes between the two groups.

4.4. Limitations and implications for further research and clinical practice

Although this study has limitations in establishing a definitive causal relationship between acupuncture treatment and reduced mortality in patients with IPD, the findings suggest that acupuncture exposure may be associated with a decrease in mortality. Therefore, integrating acupuncture into PD management from the time of diagnosis could be considered for improving long-term prognosis. While this study does not provide conclusive evidence regarding the impact of acupuncture on complications and prognostic factors, such as fractures, emergencies, and DBS implementation, previous RCTs and observational studies using real-world data on acupuncture in patients with IPD may serve as a reference for its potential clinical application. This study has several limitations, and we aim to propose improvements for future research to address these issues. First, this study alone cannot clearly determine whether acupuncture treatment has a causal relationship with reduced mortality. We found that acupuncture exposure was associated with a reduced mortality rate in patients with IPD. When mobility is impaired, access to acupuncture treatment becomes more complex, often requiring home visits or hospitalization. To control for variables, only non-disabled patients who had not received a disability rating at the time of the initial diagnosis were analyzed. However, the severity of symptoms or disease stage between those who received acupuncture and those who did not may not have been matched 1:1 solely based on the disability rating. According to a survey of patients with IPD, those seeking complementary and alternative medicine were aiming to address motor symptoms, fatigue, pain, and constipation, and these patients often experienced significant discomfort due to either motor or non-motor symptoms caused by IPD.⁵⁴ Patients with higher levodopa doses may seek acupuncture treatment more frequently due to the burden of comorbid symptoms or complications. In this study, the proportion of individuals with a CCI score ≥3 was higher in the acupuncture group than in the non-exposed group before matching, suggesting that the general condition of the acupuncture group may have been worse. Conversely, patients with relatively milder motor symptoms and a wider range of daily activities may find it easier to receive regular acupuncture treatment. In other words, it is also possible that patients with better general conditions, higher mobility, and greater freedom of movement were more likely to receive acupuncture treatment. Further research is needed to examine how the characteristics of patients who frequently receive acupuncture differ from those who do not, not only in the general disease population but also specifically within the PD patient group. Second, this study investigated the long-term prognosis of patients with early IPD who were exposed to acupuncture at the onset of the disease. Due to East Asian culture, which is more favorable to acupuncture, it was not feasible to design a new acupuncture user cohort study design. The appropriate washout period for acupuncture treatment has not been clearly established. In this study, patients who received acupuncture for 6 months were excluded to eliminate any residual effects of acupuncture. In recent RCTs, there is a tendency to exclude individuals who received acupuncture within the last 3–6 weeks.⁵⁵ In terms of pain, acupuncture is estimated to maintain its effects for 3–4 weeks when compared to sham acupuncture.⁵⁶ Meanwhile, a study on patients with PD that combined acupuncture and bee venom therapy demonstrated continuous improvement in UPDRS scores up to the 20th week, even after the 8-week treatment period had ended.⁵⁷ This suggests that the effects of acupuncture may persist for approximately 3 months. Thus, the 6 months in this study is considered a sufficient washout period. Further research is needed to determine the appropriate washout period for acupuncture treatment in studies utilizing claims data. Third, a limitation of this cohort study is the absence of a clearly established standard for defining acupuncture exposure in retrospective cohort studies using national health insurance claims data. In this study, we defined acupuncture exposure as receiving six or more acupuncture sessions within one year following a diagnosis of Parkinson’s disease. This threshold was determined based on previous retrospective cohort studies, particularly those conducted in Taiwan using similar health insurance data, where a cut-off of six sessions has been widely adopted to explore associations between acupuncture exposure and clinical outcomes. For instance, studies investigating conditions such as stroke, insomnia, and Parkinson’s disease have commonly used this six-session threshold to classify patients as having received a minimum meaningful level of acupuncture treatment.^27,28,58,59 In these studies, receiving fewer than six sessions was generally considered inadequate to expect clinical effects and was excluded to minimize the risk of misclassification bias. Although some earlier research adopted lower thresholds (e.g., two sessions), we considered these to be too permissive to reliably indicate meaningful exposure. Therefore, we employed a more conservative and evidence-based approach by setting the threshold at six sessions. Nonetheless, we recognize that the optimal number of acupuncture sessions for defining meaningful exposure may vary depending on the specific condition and treatment context. Further research involving sensitivity analyses or dose–response modelling will be necessary to refine this definition, which lies beyond the scope of the present study. Finally, since the data were not linked to the electronic medical record (EMR), individual PD symptoms and related details were not included in the analysis. For instance, it was difficult to extract detailed information on specific medications, and the types of acupuncture treatments, such as which points or acupoints were applied, were not discernible. Acupuncture treatments vary widely, including options like pharmacopuncture, moxibustion, thread-embedding acupuncture, and laser acupuncture. Notably, bee venom acupuncture has shown effects in preventing neuron cell death, which helps improve motor symptoms.⁵⁷ Since acupuncture treatments not covered by insurance, such as bee-venom acupuncture and acupotomy, could not be analyzed and it was impossible to distinguish between different types of acupuncture, further studies integrating EMR and claims data are needed to evaluate the effects of specific acupuncture methods more accurately.⁶⁰

4.5. Conclusions

The results of this study indicate that among patients with IPD, the acupuncture treatment exposed group had a lower HR for mortality (0.843, 95 % CI: 0.794−0.896), suggesting that exposure to acupuncture treatment is associated with reduced mortality. Based on our findings, we suggest the potential role of acupuncture as an important complementary treatment for improving the long-term prognosis of patients with IPD in clinical practice. However, the observed reduction in mortality in this study should be interpreted and validated in conjunction with future long-term follow-up RCTs that utilize mortality as an outcome measure.

Author contributions

Conceptualization, Methodology, Investigation: Y.-C.H and J. Leem. Software validation, Formal analysis, Resources, Data curation: J. Leem. Writing – Original Draft: Y.-C.H. Writing – Review & Editing: Y.-C.H, C.-N.K, J. Leem, H.-G.L, S.K, S.-Y.C, W.-S.J, S.-G.M, S.-U.P, and J.-M.P. Supervision: J. Leem and C.-N.K. Visualization: Y.-C.H. Project administration: Y.-C.H, C.-N.K and J. Leem. Funding acquisition: J. Leem.

Conflict of interest

The authors declare that they have no conflicts of interest.

Funding

This paper was supported by Wonkwang University in 2025.

Ethical statement

This study was approved for exemption from review by the Institutional Review Board of Kyung Hee University Hospital at Gangdong (KHNMCOH 2023–01–004).

Data availability

Data sharing is limited in compliance with privacy requirements, and the NHIS forbids the transfer, renting, or sale of datasets to other organizations. Researchers can request NHIS data from their official website (https://nhiss.nhis.or.kr) if granted access.