Pain is a common non-motor symptom in Parkinson’s disease (PD), and research has been increasing in recent years. The prevalence of pain in patients with Parkinson’s disease ranges from 40% to 85%, and is higher than in same-age controls. The literature has shown that the pain group in Parkinson’s disease has an earlier onset and longer duration of disease compared with the pain-free group of the same age, and that the UPDRS III score, H-Y score, HRSD, HAMA score, and levodopa dose are all higher than those of the pain-free group, with statistically significant differences. However, compared to the large amount of epidemiological data, domestic reports on clinical diagnosis and treatment are sporadic. In order to increase clinicians’ understanding of pain in Parkinson’s disease, this article focuses on three aspects of clinical manifestations, diagnosis and treatment.
I. Clinical manifestations
The manifestations of pain in Parkinson’s disease are diverse, and the available literature reports include low back pain, frozen shoulder, ankle spasm pain arthralgia, burning pain in the mouth, and abdominal pain. There are 5 commonly mentioned categories: musculoskeletal pain, dystonia-related pain, radicular pain, central pain, and sedentary pain.
Musculoskeletal pain: Musculoskeletal pain includes muscle spasticity and arthralgia. Spastic pain occurs in the paraspinal, neck and calf muscles, while arthralgia occurs in the shoulder, hip, knee and ankle joints. Musculoskeletal pain is usually associated with soreness and is considered to be a cumulative effect of lactic acid caused by persistent muscle spasm. In particular, “frozen shoulder” is typical and presents with limited range of motion of the shoulder joint, usually with localized pain. A retrospective study suggests that the onset of “frozen shoulder” precedes the typical Parkinson’s disease motor symptoms and is closely associated with the more severe side of the motor symptoms.
Dystonia-related pain: Dystonia-related pain is characterized by tonic muscle pain with localized postural abnormalities that can occur in the ankles, face, neck, abdomen, and back and resolve with activity. This type of pain can be caused by fluctuations in motor symptoms due to anti-Parkinsonian medications and usually occurs in the off phase, especially in the morning when the medication is not taken. Open-phase pain includes peak-dose dystonia and biphasic dystonia.
Neurogenic pain: Neurogenic pain presents as radiating sharp pain, often with numbness and tingling in the fingers and toes, usually confined to the area innervated by a nerve root. This type of pain is associated with compression of spinal nerve roots due to lumbar disc herniation, with panic gait, kyphosis and dystonia as possible causes.
Central pain: Central pain manifests in a variety of ways, including persistent dull pain, tingling-like pain, burning pain, or a tightening sensation in the fascia, sometimes with transient knife-like or electric shock-like episodes of acute pain, often with varying degrees of somatic sensory abnormalities. The degree of pain is moderate to severe, even unbearable, and may fluctuate with mood swings. Central pain is difficult to localize, such as half of the torso, or the lower body, and may involve one hand or the radial side of the hand or half of the face, or even the perineum.
Sedentary pain: uncontrollable inability to sit still, walk repeatedly, or walk in place, often at night. The inability to sit still is a subjective internal feeling of restlessness and the need to move, manifested in two ways: an objective overall internal state of restless movement; and a subjective desire to move and the need to walk to relieve symptoms.
Other forms of pain: typical of these are hanger pain, abdominal pain, and burning pain in the lips. In Parkinson’s disease patients with postural hypotension, the pain radiates from the back of the neck to the occipital and shoulder muscles, and the pain area is shaped like a coat hanger. This type of pain may decrease with the resolution of postural hypotension. Abdominal pain in patients with Parkinson’s disease is often difficult to localize and is most often related to their vegetative dysfunction. In addition, pain may be an adverse effect of anti-Parkinsonian drugs. In one case report, a 65-year-old woman had burning lip pain that could develop after taking levodopa and disappeared after stopping levodopa.
Diagnosis and differential diagnosis
There is no uniform diagnostic standard for Parkinson’s disease-related pain at home and abroad, and the clinical diagnosis is mostly exclusionary. Secondly, the correlation between pain and Parkinson’s disease must be clearly defined; secondly, other causes of pain, such as spinal diseases, lumbar disc herniation, neuroinflammatory diseases, etc., must be excluded in order to diagnose Parkinson’s disease-related pain. Finally, a classification of Parkinson’s disease-related pain is also required.
Although basic research has shown that Parkinson’s disease can lead to alterations in nociceptive thresholds, the clinical diagnosis still relies on the medical history. Musculoskeletal pain is associated with motor symptoms such as myotonia, bradykinesia, and postural dysreflexia, and pain is more pronounced at the site of motor symptoms, such as arthralgia that is exacerbated with myotonia. The incidence of this type of pain is higher in the off phase of motor symptoms than in the on phase, and it worsens as the disease progresses. The patients’ motor symptoms and musculoskeletal pain were relieved simultaneously after taking anti-Parkinson’s disease drugs. Central pain correlates with Parkinson’s disease depression and is effective with antidepressants. In addition, some pain is an adverse effect of anti-Parkinson’s disease drugs, and discontinuation or adjustment of the dosing regimen can effectively improve this type of pain.
The diagnosis of Parkinson’s disease-related pain must exclude other causes of pain. For Parkinson’s disease patients with chronic pain, arthralgia must be differentiated from rheumatoid arthritis; back pain must be differentiated from radicular pain if ankylosing spondylitis is excluded; radicular pain must be differentiated from simple lumbar disc herniation, lumbar strain, and herpes zoster. Sedentary pain should be differentiated from restless leg syndrome, which is characterized by unbearable painful abnormal sensations in the lower extremities. Central pain associated with Parkinson’s disease must be excluded from other causes, such as simple episodic headache, headache due to psychiatric factors, traumatic brain injury, meningitis, cerebral ischemia, etc. Relevant medical history and imaging examination can help in the differential diagnosis.
A clear categorization of pain is needed because of the different treatment preferences. In 1998 Ford classified pain in patients with Parkinson’s disease into five categories (musculoskeletal, neurogenic, dystonia-related, central, and sedentary) based on patient description. In 2012 Wasner and Deuschl proposed a novel and detailed classification system. Firstly, pain was classified according to its relevance to Parkinson’s disease. Secondly, Parkinson’s disease-related pain was subdivided into irritant pain (musculoskeletal pain, visceral pain, skin pain), neurogenic pain (neurogenic pain, central pain) and mixed pain based on the cause of pain. Among these musculoskeletal pains include dystonia-related pain and typical shoulder and back pain. This classification system states that Parkinson’s disease-related pain responds well to antiparkinsonian medications and that there is a different bias in the treatment of irritant pain versus central pain. However, accurate classification is still difficult in clinical practice.
III. Treatment
There is no uniform treatment plan for pain occurring in patients with Parkinson’s disease, and clinical treatment is more empirical. Epidemiological studies have shown that the majority of patients with Parkinson’s disease who need and want to have analgesic treatment are in the middle and late stages of Parkinson’s disease. These patients have been on medication for many years and have established treatment regimens, with levodopa compounded as the primary drug and other drugs at higher doses, with motor complications and a variety of non-motor symptoms. Therefore, the treatment should be coordinated with the patient’s existing treatment plan and take into account the patient’s other symptoms, and the treatment principles and treatment goals should be referred to the Chinese Parkinson’s Disease Treatment Guidelines. Treatment is divided into two categories: pharmacological and non-pharmacological.
Pharmacological treatment
The treatment of Parkinson’s-related pain is based on the patient’s original medication regimen. Anti-Parkinsonian medications are effective for most Parkinson’s disease-related pain, especially pain related to motor symptoms, such as low back muscle pain. In addition, analgesics such as non-relaxant analgesics and botulinum toxin are effective in reducing irritant pain such as arthralgia and early morning foot muscle tonic pain. For central pain, trials have confirmed the efficacy of duloxetine. Orthopedic treatment has been reported to be effective in relieving neurogenic pain. They are described below separately by drug type.
Anti-Parkinsonian drugs: With a clear diagnosis, pain triggered by anti-Parkinsonian drugs should first be discontinued or the drug dose reduced or switched to a long-acting dopamine agonist or controlled-release levodopa. For pain that is positively correlated with motor symptoms, anti-Parkinsonian drugs should be preferred. For dystonic pain in the “off” phase, the duration of pain can be reduced by shortening the “off” phase strategy. The adverse effects of dopamine agonists are similar to those of levodopa, with the exception of a low incidence of symptom fluctuations and allodynia and a high incidence of postural hypotension and psychiatric symptoms. Therefore, for head and neck pain secondary to postural hypotension, the adverse effects of dopamine agonists should be considered, while for pain associated with symptom fluctuations, the dosage of levodopa may be reduced accordingly, and a dopamine agonist may be added or switched.
Studies on the analgesic effects of anti-Parkinsonian drugs have been reported mostly with dopaminergic drugs, with drugs including levodopa, rotigotine, pramipexole, and apomorphine. Levodopa significantly increased non-motor symptom scale scores, which include symptoms such as pain. The degree of pain reduction was positively correlated with the degree of motor symptom relief. However, there are no clear studies on whether levodopa has a direct analgesic effect or whether pain relief is achieved only by controlling motor symptoms. A double-blind, placebo-controlled trial of 297 Parkinson’s disease patients with poorly controlled early morning motor symptoms found significant pain improvement in the rotigotine group compared with the placebo group. In one case report, pramipexole was effective in improving burning lip pain in a 68-year-old woman. Also, in a group of case reports (including one with pelvic pain and two with early morning myalgic pain), apomorphine was significantly effective in refractory off-phase pain. In addition, apomorphine showed significant relief of sedentary inability pain.
Central medications: Epidemiological studies have shown a positive correlation between pain and depression in PD patients. 5-hydroxytryptamine reuptake inhibitors have been shown to be effective for pain in patients with comorbid depression, which is mostly centralized or somatized pain. Duloxetine is a well-studied drug with clear analgesic effects in recent years. In an open trial, 65% of 23 patients with Parkinson’s disease showed subjective pain relief after duloxetine administration, and pain thresholds did not change. However, due to the uncontrolled nature of open trials, the efficacy of duloxetine needs to be confirmed in more clinical trials.
Other drugs: Non-retaining analgesics have been used clinically to relieve arthralgia and radicular pain in patients with Parkinson’s disease, suggesting that these pains may be associated with an in vivo immune response. Botulinum toxin injections have been shown to be effective in the treatment of dystonia-related pain, possibly due to the neuroleptic effects of botulinum toxin. A double-blind, randomized controlled study of 45 Parkinson’s disease patients with foot dystonia-related pain showed that botulinum toxin injections relieved dystonia and foot dystonia-related pain.
Non-pharmacological treatment
Non-pharmacologic treatments are currently used in patients with Parkinson’s disease that is poorly controlled by medications, such as central pain that is difficult to localize and refractory off phase pain. Due to the ethical issues involved in this type of treatment, most of the current studies are open studies, and it is difficult to do randomized double-blind comfort-controlled studies, so the effectiveness and safety of this treatment is yet to be confirmed. Treatment modalities include destructive surgery and brain stimulation, the latter of which is divided into invasive and non-invasive.
Destructive surgery: Destructive surgery was used early and is still used because of the high damage, but the adverse effects are relatively large. In a study by Baron et al. of 12 patients with Parkinson’s disease who underwent pallidum destruction, 10 of them showed a significant reduction in UPDRS scores and a significant improvement in pain and discomfort after surgery. In contrast, a prospective study by Honey et al. showed that somatization pain increased in patients at 6 weeks postoperatively, while musculoskeletal pain and dystonia-related pain were significantly relieved, with no significant change in sensory disorder pain, with the same results after 1 year of follow-up. Since the site of destruction and the specific surgical procedure are not yet standardized, it is difficult to fully evaluate the efficacy of the procedure, and further verification of the long-term efficacy of the procedure is needed.
Deep brain stimulation (DBS): DBS is performed by implanting wires at specific locations in the brain and using electrical stimulation from a brain rhythm device to achieve therapeutic goals. A study of 29 Parkinson’s patients treated with DBS showed that DBS was most effective for dystonia-related pain, which disappeared almost completely, followed by neuropathic pain (92% relief), then neurogenic pain (63%), and musculoskeletal pain (61%). In addition, DBS was equally effective in treating non-Parkinson’s disease-related pain before treatment.
Non-invasive brain stimulation: The main techniques are repetitive transcranial magnetic stimulation (rTMS) and cranialelectrotherapy stimulation (CES). rTMS works by applying pulsed magnetic fields to brain tissue to induce a certain intensity of stimulation. rTMS induces a certain intensity of induced currents through pulsed magnetic fields on brain tissue, while CES is a technique that directly conducts a weak micro-bioelectric current to the brain via the temporal region of the skull. There are case reports suggesting that rTMS is effective in relieving off-phase dystonia. A randomized, double-blind, placebo-controlled trial suggests that CES has a significant non-specific relief effect on chronic pain. The non-invasive advantage makes these two treatment modalities a trend, however, efficacy is related to many factors such as stimulation frequency, and its effectiveness still needs further confirmation.
Timely diagnosis and treatment of Parkinson’s disease-associated pain can help improve the symptoms and quality of life of patients with Parkinson’s disease. In contrast, there are still no uniform diagnostic criteria for Parkinson’s disease-related pain, and its treatment is mostly based on empirical data and lacks evidence from controlled studies. Therefore, research on pain in Parkinson’s disease still needs further improvement.