Peripheral sensitization is demonstrated in subacromial pain syndrome, with central sensitization found only in females

Abstract

The objective of this study was to explore whether hypersensitivity in patients with subacromial pain syndrome manifests purely as localized peripheral sensitization or central sensitization, is influenced by the presence of subacromial pain, and presents similarly in male and female patients. Pressure pain threshold was assessed in both a patient cohort with unilateral subacromial pain syndrome and an uninjured matched control group. Control subjects were tested once, while patients were assessed at baseline and after an almost instantaneous reduction in pain arising from an anesthetic injection in patients. Patients received a subacromial injection consisting of both anesthetics (3 cc of 2% lidocaine and 6 cc 0.5% Marcaine with Epinephrine) and a corticosteroid agent (1 cc DepoMedrol). Patients demonstrated hypersensitivity across the involved shoulder only, providing evidence for peripheral sensitization. There were trends for hypersensitivity across remote joints, however when separated by sex, only female patients demonstrated both peripheral and central sensitization. Immediate pain reduction had no influence on hypersensitivity in the short-term.

INTRODUCTION

Shoulder pain is one of the leading sources of chronic pain and long-term disability within the middle aged and working populations,¹ affecting between 7% and 26% of the adult population.² Approximately half of all shoulder complaints arise from a condition known as subacromial pain syndrome (SPS), otherwise known as shoulder impingement syndrome.^{1; 3}

Emerging evidence suggests that maladaptive neuroplasticity may contribute to the development or progression in subsets of the SPS population.⁴ Consistent with other chronic pain conditions, patients with SPS have consistently been observed to have hypersensitivity across the symptomatic shoulder,^5–8 providing evidence that peripheral sensitization contributes to subacromial pain. However it is less clear if central sensitization is present in the SPS population, as remote locations, including the asymptomatic shoulder^{5; 8; 9} and lower extremities^{5; 7–9} have shown inconsistent hypersensitivity to pain. The presence of central sensitization suggests that rather than solely being a product of peripheral tissue damage, the pain associated with SPS may have a central contribution.

Females with rotator cuff pathology suffer from higher levels of disability and pain compared to males, both prior to and after receiving treatment.¹⁰ To our knowledge, no previous studies have assessed whether the development of central sensitization is dependent upon sex in a population with SPS. This knowledge gap is surprising given the fact that females are known to be more susceptible to the development of central sensitization than males in other chronic pain conditions.¹¹

It is currently unknown whether peripheral or central sensitization persist after the reduction of subacromial pain. In a previous study, after a physical therapy regime, patients with SPS demonstrated reduced hypersensitivity at the involved shoulder and contralateral shoulder, but not the lower extremity post-treatment.¹² Another study demonstrated that patients who presented with greater levels of central sensitization prior to treatment reported greater pain intensity post-treatment.⁶ This finding is not surprising given that several studies have shown a patient’s current pain intensity is highly correlated to central sensitization level.^{7; 13} A modulation of central sensitization is associated with the acute removal of pain in other chronic conditions,¹⁴ suggesting that central sensitization is dynamic and responsive to the influence of peripheral nociceptors.

The primary aim of the present study was to assess peripheral and central sensitization by testing hypersensitivity at involved and remote locations in patients with SPS, both before and after acute pain reduction. The secondary aim of the present study was to explore characteristics associated with the presence of central sensitization. We hypothesized that patients with SPS would demonstrate a greater sensitivity to pain at the symptomatic shoulder and remote locations (contralateral shoulder, both knees) than matched controls. We further hypothesized that upon pain reduction, patients experiencing SPS would demonstrate decreased sensitivity to pain at both shoulders and both knees relative to pre-injection values. Finally, we hypothesized that after controlling for pain duration and pain intensity, female patients would demonstrate greater sensitivity than male patients.

METHODS

Participants

The Institutional Review Board approved this case-control study (level III). Informed consent was obtained from a sample of convenience of 20 patients (10 females) with unilateral SPS and 20 healthy age-, sex-, and arm dominance-matched controls. Prior to recruitment, patients were diagnosed with stage II impingement by an orthopaedic surgeon and were scheduled to receive a subacromial injection as part of their treatment plan. To be diagnosed with stage II impingement, patients must have demonstrated a positive sign to the treating physician on at least three of the following five manual tests prior to receiving the injection: Hawkins-Kennedy, Neer, painful arc, empty can (Jobe), and painful external rotation resistance. Exclusion criteria for patients included a positive Spurling test, shoulder dislocation within the past three months, reproduction of shoulder pain with active or passive cervical range of motion, and signs of a rotator cuff tear on manual tests or imaging. Participants were excluded if either shoulder had a history of glenohumeral osteoarthritis, humeral head fractures, glenohumeral arthroplasty, rotator cuff tears or repairs, joint laxity, or pain at rest.

Protocol

Participants were tested at two time points. Patients were first tested immediately before receiving the pain reducing subacromial injection and then again fifteen minutes after receiving the injection. For control participants, the two time points were separated by a fifteen-minute rest period. Subacromial injections for patient participants were administered by the same physician utilizing an 18 gauge needle and an anterolateral approach. The subacromial injection consisted of both anesthetics (3 cc of 2% lidocaine and 6 cc 0.5% Marcaine with Epinephrine) and a corticosteroid agent (1 cc DepoMedrol).

Questionnaires

The DASH (disabilities of the arm, shoulder, and hand) questionnaire was administered to patients and controls prior to the testing to measure physical function and symptoms affecting the upper extremities.¹⁵ Pain intensity was measured by utilizing a series of visual analog scores that asked the participants to indicate the highest pain intensity they experienced during a series of three maximum voluntary isometric contractions (MVICs) at the involved shoulder. The results were scored from 0–10 centimeters (0 cm = no pain, 10 cm = worst pain imaginable) in increments of one millimeter.

Pain Sensitivity

Pain sensitivity was tested at four locations including the ipsilateral shoulder, contralateral shoulder, ipsilateral knee, and contralateral knee utilizing a pressure pain threshold (PPT) protocol. Measures of PPT, defined as the minimum force applied that induced pain, were obtained by utilizing a hand-held pressure algometer with a one-cm² probe (FPIX, Wagner Instruments). With participants in a seated position, upper extremity assessment sites were marked at the bilateral deltoid muscles, at the midpoint between the flat portion of the acromion and deltoid insertion (figure 1A). With participants in standing position, lower extremity assessment sites were marked at the bilateral vastus lateralis muscle, approximately five inches superior from the lateral edge of the patella (figure 1B). The probe was positioned perpendicular to the assessment site and pressure was applied at a rate of approximately one kg/s. The participant informed the assessor when they first perceived a sensation of pain or discomfort, at which point pressure application ceased and the PPT value was noted.

Figure 1.

Experimental set-up used for pressure pain threshold (PPT) measurements during the subacromial pain study. A) Deltoid location. B) Vastus lateralis location.

The order of testing was randomized between participants. Four measurements were obtained for each location with a 30 second interval between measurements. The change in PPT scores was calculated for each joint by subtracting mean first session PPT scores from mean second session PPT scores.

Statistical Analysis

Participant Characteristics

Independent t-tests were used to compare patient and control characteristics as well as male and female patient characteristics. Dependent t-tests were used to compare session 1 and session 2 pain scores.

Pre-injection Sensitivity

A single two-way mixed model ANOVA (Participant Group × Joint) was used with PPT score as the dependent variable. An a priori interaction contrast was also run for PPT scores to assess whether the differences between PPT scores for patient and control participants were different between the involved shoulder and remote joints. The a priori interaction contrast was coded as a group (patient = 1, control = −1) by joint (ipsilateral shoulder = 3, contralateral shoulder = −1, ipsilateral knee = −1, contralateral knee = −1) interaction.

Post-injection vs. Pre-injection Sensitivity

A single two-way mixed model ANOVA (Participant Group × Joint) was used with the dependent variable being change in PPT scores. An a priori interaction contrast was also run for change in PPT scores to assess whether the differences between PPT scores for patient and control participants were different between the involved shoulder and remote joints. The a priori interaction contrast was coded as a group (patient = 1, control = −1) by joint (ipsilateral shoulder = 3, contralateral shoulder = −1, ipsilateral knee = −1, contralateral knee = −1) interaction.

Within-Group Differences

Four hierarchical multiple regression models were run, one for each joint (patient data only). Standardized z-scores for PPT values were the dependent variable. Pain duration, pain intensity and sex were the independent variables. Pain duration and pain intensity were added to the model first, while sex was added to the model later to see if it increased the predictive power.

RESULTS

Participant Characteristics

There were no significant differences between patients and controls with respect to age, body mass index, height or weight (all p>0.05). DASH and pre- and post-injection visual analog scores were significantly higher in patients compared to controls (all p<0.001, table 1). There were no significant differences between male and female patients with respect to age, body mass index, DASH scores, pre-injection visual analog scores, or post-injection visual analog scores (all p>0.05). The subacromial injection resulted in a marked reduction in pain for patients (p<0.001) resulting in a mean 54% reduction in pain scores.

Table 1.

Characteristics of Patients with Subacromial Pain Syndrome and Controls.

	Controls	Patients
Group	All	All	Males	Females
Sex
Males	10	10	10	--
Females	10	10	--	10
Demographics
Age (years)	52 ± 10	51 ± 10	52 ± 8	51 ± 11
Height (cm)+	171 ± 10	169 ± 10	176 ± 10	163 ± 7
Weight (kg)+	80 ± 17	86 ± 18	97 ± 16	76 ± 15
BMI	27 ± 4	30 ± 5	31 ± 5	29 ± 4
Joints
Dominant Arm (Right/Left)	16 / 4	16 / 4	9 / 1	7 / 3
Dominant Leg (Right/Left)	16 / 4	16 / 4	9 / 1	7 / 3
Injured Shoulder (Dominant/Non-dominant)	------	6 / 14	2 / 8	4 / 6
Pain
DASH*	2.6 ± 3.6	38.6 ± 16.8	36.8 ± 22.9	40.3 ± 7.5
Pre-injection VAS (0–10)*	0.0 ± 0.1	6.5 ± 2.6	7.0 ± 2.2	6.0 ± 2.9
Post-injection VAS (0–10)*	0.0 ± 0.1	2.9 ± 1.4	3.4 ± 1.6	2.6 ± 0.8

^*Denotes a significant difference between patients with SPS and controls at p < 0.05.

⁺Denotes a significant difference between male and female patients with SPS at p < 0.05.

Pre-injection Sensitivity

The a priori interaction comparison was significant (p<0.01), revealing that differences in patients and controls PPT scores were location dependent (involved joint versus remote joints). PPT scores at the involved shoulder were significantly smaller (p=0.02) in patients (Mean=2.9 kg) versus controls (Mean=4.1 kg), with a mean difference of 1.2 kg (figure 2). Across all three remote joints, patients demonstrated lower PPT scores than controls, with mean between group differences of 0.5 kg (figure 2). These between-group differences were not significant, neither when the remote joints were pooled into one composite score (p=0.38) nor when individual joints were analyzed including the contralateral shoulder (p=0.29), ipsilateral knee (p=0.43), and contralateral knee (p=0.49). The a priori paired t-test revealed that PPT scores were significantly lower (p<0.01) at patients’ involved (Mean=2.9 kg) versus contralateral shoulder (Mean=3.4 kg), with a mean side-to-side difference of 0.5 kg (figure 2).

Figure 2.

Pre-injection pressure pain threshold (PPT) scores (means ± SEMs) for patients with SPS and controls. Analyzed joints include the involved shoulder (IS), contralateral shoulder (CS), ipsilateral knee (IK), contralateral knee (CK), and average of the CS, IK, and CK joints (Remote). * Denotes a significant between-group difference. + Denotes a significant within-group difference.

Post-injection Sensitivity

For the change in PPT scores after treatment, the a priori interaction comparison was significant (p<0.05), revealing that differences between change scores in patients and controls were location dependent (involved joint versus remote joints). Change scores at the involved shoulder were on average 0.3 kg greater in patients, however this between-group difference did not reach significance (p=0.18) (figure 3). Across the three remote joints, patients and controls demonstrated similar change scores (mean between-group difference = 0.1 kg). Pairwise comparisons confirmed that between-group differences were not significant neither when the remote joints were pooled into one composite score (p=0.68) nor when individual remote joints were analyzed including the contralateral shoulder (p=0.22), ipsilateral knee (p=0.69), and contralateral knee (p=0.96).

Figure 3.

Change in pressure pain threshold (PPT) scores (means ± SEMs) for patients with SPS and controls following the injection/rest period. Analyzed joints include the involved shoulder (IS), contralateral shoulder (CS), ipsilateral knee (IK), contralateral knee (CK), and average of the CS, IK, and CK joints (Remote).

Within-Group Differences

For each of the four joints (involved shoulder, contralateral shoulder, ipsilateral knee, contralateral knee), the associated regression model incorporating only pain duration and pain intensity was non-significant (all p>0.05), however the addition of sex to the model significantly improved the prediction of standardized z-scores (all p<0.01). Therefore, a simpler model incorporating only the main effects of sex (Male = 0, Female = 1) was examined to determine how sex predicted z-scores (table 2). For each joint, sex alone predicted over 44% of the variance in z-scores (R² range: 0.44 to 0.59, all p<0.01), and for all four joints, female patients’ z-scores were predicted to be significantly smaller than males (β range: −1.26 to −1.81, all p<0.01). Moreover, follow-up one sample t-tests revealed z-scores for males were not significantly different from zero at the involved shoulder (p=0.55), non-involved shoulder (p=0.59), ipsilateral knee (p=0.21), or contralateral knee (p=0.27) (figure 4). Follow-up one sample t-tests revealed z-scores for females were significantly different from zero at the involved shoulder (p<0.001), non-involved shoulder (p<0.001), ipsilateral knee (p<0.01) and contralateral knee (p<0.01) (figure 4).

Table 2.

Regression Results for Standardized Pain Pressure Threshold (PPT) Z-scores for Male and Female Patients.

	Involved Shoulder		Contralateral Shoulder		Ipsilateral Knee		Contralateral Knee
	B a	SE B b	B	SE B	B	SE B	B	SE B
1st Model
Pain Duration (months)	0.00	0.01	0.00	0.01	0.00	0.01	0.01	0.01
Pain Intensity (VAS 1–10)	0.00	0.11	0.13	0.12	0.11	0.08	0.15	0.11
R2	0.01		0.06		0.11		0.15
2nd Model
Pain Duration (months)	−0.01	0.01	−0.01	0.01	0.00	0.01	0.00	0.01
Pain Intensity (VAS 1–10)	−0.08	0.07	0.05	0.09	0.06	0.07	0.09	0.09
Sex (0 = male; 1 = female)	−2.02**	0.37	−1.83*	0.49	−1.22*	0.34	−1.55*	0.71
ΔR2	0.66**		0.44*		0.39*		0.33*
3rd Model
Constant	−0.19	0.25	0.24	0.33	0.24	0.22	0.30	0.32
Sex (0 = male; 1 = female)	−1.81**	0.36	−1.75*	0.46	−1.26*	0.32	−1.70*	0.45
R2	0.59**		0.44*		0.47*		0.44*

^aB is the unstandardized beta, and represents the slope of the line between the independent and dependent variables.

^bSE B is the standard error for the unstandardized beta.

^*Denotes significance at p < 0.01.

^**Denotes significance at p < 0.00

Figure 4.

Pain pressure threshold (PPT) z-scores for male and female patients. A) Involved shoulder. B) Contralateral shoulder. C) Ipsilateral knee. D) Contralateral knee. Circles represent individual scores while diamonds represent group means. + Denotes a significant difference between male and female patients. * Denotes a significant difference from a one-sample test value of 0.

DISCUSSION

The aims of the present study were three-fold. First, we examined whether patients with SPS would exhibit characteristics of peripheral and central sensitization by looking at sensitivity across the involved shoulder as well as remote joints. Second, we assessed the effects of pain reduction (via an anesthetic injection) on sensitivity at the involved shoulder as well as remote joints. Lastly, we explored characteristics associated with the presence of peripheral and central sensitization.

Pre-injection Sensitization

The hypothesis that patients would demonstrate greater hypersensitivity than controls at the symptomatic shoulder as well as remote joints was not supported. Our results demonstrated that patients had significantly lower PPT values at the involved shoulder only (figure 2) in comparison to controls. While lower PPT scores were observed at remote joints, these differences did not reach significance. The patients’ involved shoulder had significantly lower PPT values compared to the contralateral shoulder, with a mean side-to-side difference of 0.5 kg. Consequently, there was evidence for peripheral sensitization within our patient cohort, however evidence for peripheral and central sensitization could not be supported within the cohort as a whole.

Previous studies have also demonstrated smaller PPTs on the order of 0.9–1.0 kg when the involved deltoid of patients was compared to controls. In contrast to the present study, these studies also demonstrated significantly smaller PPTs across the contralateral deltoid and lower extremities,^{5; 8} suggesting that both peripheral and central sensitization were present in these patient cohorts. Collectively, these findings suggest that peripheral sensitization may be a general feature of SPS while central sensitization may only be present in subsets of the population. Consequently, it may be overly simplistic to classify SPS as a localized musculoskeletal disorder of the shoulder, where the primary etiology of pain is mechanical stimulation and inflammation. Instead, the existence of neuropathic pain components may be present in some patients with SPS. Correct identification of localized or neuropathic pain in musculoskeletal disorders enables the introduction of the appropriate treatment for musculoskeletal pain.

Post-injection Sensitization

The hypothesis that pain reduction would result in decreased sensitivity across the involved shoulder and remote joints, was not supported. Despite a reduction in perceived pain, no changes in sensitivity were observed following the injection (figure 3), neither at the involved shoulder nor at remote joints. Consequently, even after reducing pain by blocking localized nociceptors in the subacromial space, peripheral sensitization was still present in patients.

To our knowledge, only one previous study has assessed the influence of a pain reducing treatment on PPT scores in a population with SPS. In contrast to the present study, Camargo et al.¹² demonstrated that both the symptomatic and contralateral shoulders demonstrated greater PPTs in the post-treatment session compared to the pre-treatment session, providing evidence that peripheral sensitization and perhaps peripheral sensitization were reversed after the reduction of pain. However, the present study assessed patients only 15 minutes after pain reduction induced via an anesthetic injection while Camargo et al. studied patients after four weeks of physical therapy intervention. Together, these results suggest that the etiology of shoulder pain in patients with SPS may be multi-factorial, with a mixture of localized nociceptive and neuropathic components. Moreover, peripheral sensitization when not paired with central sensitization seems to be reversible in SPS, but not immediately following the reduction of pain. It is less clear how central sensitization might be influenced by localized pain reduction.

Sex Differences in Sensitization

The hypothesis that after controlling for pain duration and pain intensity, female patients would demonstrate greater sensitivity than males, was supported. Our results revealed significantly greater z-scores in female compared to male patients at both the involved and remote joints, suggesting that the development of peripheral and central sensitization in the SPS population may be sex specific. Interestingly, pain intensity and pain duration did not demonstrate a significant correlation with z-scores, suggesting that greater sensitization was not present in those with greater pain intensity or prolonged pain. This suggests that neither the presence of peripheral nor central sensitization could be supported within our male only patient population, while the presence of both peripheral and central sensitization were supported within our female only patient population.

Sex disparities exist among populations with shoulder pain in regards to treatment outcomes, with female patients experiencing a higher prevalence of repeat injuries and greater levels of disability after treatment than male patients.^{10; 16} Our results suggest that one possible factor contributing to the higher incidence of subacromial pain and poor outcomes in female patients, is that central sensitization is more prevalent in female patients with SPS.

Study Limitations

There are several limitations to the present study. Only one quantitative sensory test (PPT) was utilized in this study as a proxy to assess the presence of peripheral and central sensitization. It is possible that other quantitative sensory tests such as heat or cold tolerance would yield different conclusions about the association between subacromial pain and sensitization. Also, there may be a difference between the acute and prolonged reduction of pain, therefore future studies are needed to look at the long-term effects of pain reduction on sensitization.

CONCLUSIONS

In the present study as a whole, patients with SPS demonstrated hypersensitivity across the involved shoulder, providing evidence for peripheral sensitization, while remote joints demonstrated hypersensitivity that did not reach statistical significance. However, when patients with SPS were separated by sex, females demonstrated both peripheral and central sensitization. Taken together, these findings suggest peripheral sensitization is associated with SPS while substantial heterogeneity likely exists with respect to central sensitization, and one factor contributing to this heterogeneity may be sex. Moreover, pain reduction had no influence on sensitivity. The presence of central sensitization and neuropathic components in subpopulations with SPS, may hold particular promise for developing novel interventions aimed at treating SPS. Consequently, further studies are required to investigate which characteristics are associated with the development of peripheral vs central sensitization as well as the influence of long-term pain reduction on peripheral and central sensitization.

Clinical Significance –

Neuropathic components are likely present in some patients with subacromial pain syndrome, and female patients may be particularly at risk for presenting with neuropathic pain. These findings are applicable towards understanding the heterogeneous etiology underlying subacromial pain syndrome and informing clinical management.