Plantar Heel Pain is a disorder that results in pain in the heel and bottom of the foot. The pain is usually most severe with the first steps of the day or following a period of rest. Pain is also frequently brought on by bending the foot and toes up towards the shin and may be worsened by a tight Achilles tendon. The condition typically comes on slowly. In about a third of people, both legs are affected.
Plantar fasciitis is the result of degenerative irritation of the plantar fascia origin at the medial calcaneal tuberosity of the heel as well as the surrounding perifascial structures. The plantar fascia plays an important role in the normal biomechanics of the foot and is composed of three segments, all of which arise from the calcaneus. The fascia itself is important in providing support for the arch and providing shock absorption. Despite the diagnosis containing the segment “itis,” this condition is notably characterized by an absence of inflammatory cells.[rx][rx][rx]
Plantar fasciitis is a very common cause of inferior heel pain that can be triggered and aggravated by prolonged standing, walking, running and obesity, among other factors. Treatments are largely noninvasive and efficacious. Supportive treatments, including the plantar fascia-specific stretch, calf stretching, appropriate orthotics and night dorsiflexion splinting, can alleviate plantar fascia pain. While local injections of corticosteroids can help with pain relief, the effects are short-lived and must be weighed against the risk of fat pad atrophy and plantar fascia rupture.
Causes of Plantar Fasciitis
The main cause of heel pain is overstretching of the plantar fascia ligament under the foot. So why is the ligament being overstretched? There are different factors
- Over-use – too many sports, running, walking or standing for long periods (e.g. because of your job)
- Weight gain – our feet are designed to carry a ‘normal’ weight. Any excess weight places great pressure on the bones, nerves, muscles, and ligaments in the feet, which sooner or later will have consequences. Even pregnancy (in the last 10 weeks) can cause foot problems!
- Age – as we get older ligaments to become tighter & shorter and muscles become weaker; the ideal circumstances for foot problems
- Unsupportive footwear – ‘floppy’ shoes with no support as well as thongs affect our walking pattern
- Walking barefoot – especially on hard surfaces like concrete or tiles
- Low arch/flat feet or over-pronation
- Standing on your feet for several hours each day.
- Medical conditions such as rheumatoid arthritis or lupus (systemic lupus erythematosus)
- Wearing high-heeled shoes, and switching abruptly to flat shoes.
- Wearing shoes that are worn out with weak arch supports and thin soles.
- Having flat feet or an unusually high arch.
- Having legs of uneven lengths or an abnormal walk or foot position.
- Having tight Achilles tendons, or ‘heel cords’.
An important contributing factor to Plantar Fasciitis is ‘excess pronation’ (or over-pronation). This is a condition whereby the feet roll over, the arches collapse and the foot elongates. This unnatural elongation puts excess strain on the ligaments, muscles, and nerves in the foot.
When the foot is not properly aligned, the bones unlock and cause the foot to roll inward. With every step taken your foot pronates and elongates, stretching the plantar fascia and causing inflammation and pain at the attachment of the plantar fascia into the heel bone. Re-alignment of the foot should, therefore, an important part of the treatment regime.
Symptoms of Plantar Fasciitis
Pain is usually felt on the underside of the heel and is often most intense with the first steps of the day or after rest. It is commonly associated with long periods of weight bearing or sudden changes in weight bearing or activity.
You may experience
- Sharp pain in the inside part of the bottom of the heel, which may feel like a knife sticking into the bottom of the foot.
- Heel pain that tends to be worse with the first few steps after awakening, when climbing stairs or when standing on tiptoe.
- Heel pain after long periods of standing or after getting up from a seated position.
- Heel pain after, but not usually during, exercise.
- Mild swelling in the heel.
Risk factors of Plantar Fasciitis
Though plantar fasciitis can arise without an obvious cause, factors that can increase your risk of developing plantar fasciitis include:
- Age – Plantar fasciitis is most common between the ages of 40 and 60.
- Certain types of exercise – Activities that place a lot of stress on your heel and attached tissue — such as long-distance running, ballistic jumping activities, ballet dancing, and aerobic dance — can contribute to an earlier onset of plantar fasciitis.
- Foot mechanics – Being flat-footed, having a high arch or even having an abnormal pattern of walking can affect the way weight is distributed when you’re standing and put added stress on the plantar fascia.
- Obesity – Excess pounds put extra stress on your plantar fascia.
- Occupations that keep you on your feet – Factory workers, teachers and others who spend most of their work hours walking or standing on hard surfaces can damage their plantar fascia.
Intrinsic risk factors | |
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Extrinsic risk factors | |
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Principal risk factors | Causes | |
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Intrinsic | Anatomic risk |
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Functional risk |
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Degenerative risk |
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Extrinsic | Overuse |
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Incorrect training |
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Inadequate footwear |
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Diagnosis of Plantar Fasciitis
Exams and Tests
The health care provider will perform a physical exam. This may show:
- Pain on the bottom of your foot.
- Pain along the sole of the foot.
- Flat feet or high arches.
- Mild foot swelling or redness.
- Stiffness or tightness of the arch in the bottom of your foot.
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Imaging Studies
Imaging studies are typically not necessary for the diagnosis of PF.[rx,rx] In the clinical management of chronic heel pain, diagnostic imaging can provide objective information. This information can be particularly useful in cases that do not respond to first-line interventions, or when considering more invasive treatments (e.g. corticosteroid injection).
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Lateral radiograph – of the ankle should be the first imaging study. It is a good modality for assessment of heel spur, the thickness of plantar fascia, and the quality of fat pad. Stress fractures, unicameral bone cysts, and giant cell tumors are usually identified with plain radiography.[rx,rx,rx]
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Ultrasound – examination is operator-dependent, but it proves to be significant when the diagnosis is unclear.[rx,rx] In the literature, normal thickness of the plantar fascia when measured in ultrasound varies in range (mean 2–3 mm). People with chronic heel pain are likely to have a thickened plantar fascia with the associated fluid collection, and that thickness values >4.0 mm are diagnostic of plantar fasciitis.[rx]
Treatment of Plantar Fasciitis
Drugs | NSAIDs |
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Nonsurgical Treatment
More than 90% of patients with plantar fasciitis will improve within 10 months of starting simple treatment methods.
- Activity Modification – Modification of activities should be advised, while those that involve repetitive impact, such as running (even on a treadmill), should be avoided during the treatment phase. Patients can continue performing non-weight-bearing activities such as cycling, swimming, and rowing to maintain their cardiovascular fitness while minimizing cyclic loading. A gradual return to activity may be allowed after the patient is asymptomatic for 4–6 weeks and no longer has localized tenderness over the plantar fascia.
- Rest – Decreasing or even stopping the activities that make the pain worse is the first step in reducing the pain. You may need to stop athletic activities where your feet pound on hard surfaces (for example, running or step aerobics). The body is capable of healing itself and can overcome inflammation, provided you give it some rest. Avoid any running, sports, walking distances, walking up or down hills and standing for prolonged periods for at least 6 weeks. Completely avoid any barefoot walking on hard tiles and floors, especially first thing in the morning.
- Ice – Rolling your foot over a cold water bottle or ice for 20 minutes is effective. This can be done 3 to 4 times a day.
- Exercise – Plantar fasciitis is aggravated by tight muscles in your feet and calves. Stretching your calves and plantar fascia is the most effective way to relieve the pain that comes with this condition. Exercise must be done by the following system
Phase 1 exercises
- No running – walking or any other activity which causes pain either during, after or the following day.
- Night splint – wear a plantar fasciitis night splint for as long as is comfortable, overnight if possible but if you can manage 1 hour then gradually increase over time. If it is painful then remove it. Do not give up!
- Maintain fitness – by swimming or cycling and use the opportunity to work on upper body strength.
- Gentle stretching – if pain allows. Stretching the plantar fascia is essential but in addition, all the muscles of the lower leg should be stretched – including the calf muscles and the tibialis anterior at the front of the leg. Continue stretching daily throughout the rehabilitation phase and long after the injury has healed.
You are ready to move onto phase two when you can walk pain-free in the mornings.
Phase 2 treatment
The second phase of plantar fasciitis treatment aims to get the athlete back to full fitness once initial pain and inflammation has gone.
- Ice – Continue with ice after activity such as walking.
- Massage – massage techniques can be applied to further stretch and improve the elasticity of the plantar fascia. Initially, massage may be light on a daily basis but deeper techniques can be used as the condition improves. Deeper techniques may require a days recovery in between sessions.
- Ball rolling – If you are unable to see a massage therapist regularly then roll the foot over a ball or rolling pin or similar to help stretch and apply myofascial release. Do this exercise for 10 minutes per day.
Continue with this until foot fitness has been regained. If the pain becomes worse then drop back to phase 1.
Phase 2 exercises
- Stretching exercises – should be done daily if pain allows.
- Night splint – aim to wear the night splint for at least 5 hours, longer if possible.
- Walking – when you have gone at least a week with no pain then you can begin to slowly start to increase the stress on the foot. Start off by walking and increasing the distance and speed you walk until you can walk at a fast pace for at least 30 minutes with no pain. This should be a gradual process. If you feel pain at any time then go back a step.
Phase 3 – Returning to full fitness
- Ensure you have the correct shoes for your running style or sport. After every training session applies ice to the foot for about ten minutes. Ensure you stretch properly before each training session and after. Hold stretches for about 30 seconds and repeat 3-5 times.
Below is an example of a gradual return to running program. Begin each training session with a 5-minute walk followed by a stretch.
- Day 1 – walk 3 mins, jog 1 min, repeat 4 times
- Day 2 – rest
- Day 3 – walk 3 mins, jog 2 mins, repeat 4 times
- Day 4 – rest
- Day 5 – walk 2 mins, jog 3 mins, repeat 4 times
- Day 6 – rest
- Day 7 – walk 2 mins, jog 4 mins, repeat 4 times
Calf Stretch
- Lean forward against a wall with one knee straight and the heel on the ground. Place the other leg in front, with the knee bent. To stretch the calf muscles and the heel cord, push your hips toward the wall in a controlled fashion. Hold the position for 10 seconds and relax. Repeat this exercise 20 times for each foot. A strong pull in the calf should be felt during the stretch.
Plantar Fascia Stretch
- This stretch is performed in the seated position. Cross your affected foot over the knee of your other leg. Grasp the toes of your painful foot and slowly pull them toward you in a controlled fashion. If it is difficult to reach your foot, wrap a towel around your big toe to help pull your toes toward you. Place your other hand along the plantar fascia. The fascia should feel like a tight band along the bottom of your foot when stretched. Hold the stretch for 10 seconds. Repeat it 20 times for each foot. This exercise is best done in the morning before standing or walking.
Ice and Anti-Inflammatories
- Two or three times a day, apply an ice pack directly onto the heel and hold it for 5 to 10 minutes. This will help cool down the inflammation and provide temporary pain relief. Anti-inflammatory medications like Ibuprofen (found in Nurofen™ and Advil™) will help decrease the inflammation of the plantar fascia. Rapid™ is another nicely potent anti-inflammatory drug and can be helpful for temporary pain relief.
Night Splints
- Most people sleep with their feet pointed down. This relaxes the plantar fascia and is one of the reasons for morning heel pain. A night splint stretches the plantar fascia while you sleep. Although it can be difficult to sleep with, a night splint is very effective and does not have to be used once the pain is gone.
- The use of night dorsiflexion splints can also help with plantar fasciitis, especially pain that is worse during the first few steps in the morning. Night splints have produced highly positive outcomes such as the resolution of symptoms within 12 weeks of use. The patient may see improvement as early as after four weeks of use. (rx)
Orthotics
- To reduce loading of the plantar fascia on weight-bearing, orthotics should help to hold up the medial arch of the foot without placing any direct pressure on the plantar fascia. Additionally, to reduce the direct pressure of the ground on plantar fascia swelling, an aperture can be incorporated into the orthotic such that the swelling sits in the aperture.
- For athletic individuals, semi-rigid orthotics are the most practical solution, and it is helpful for physicians to specify ‘semi-rigid orthotics with plantar fascia accommodation and aperture’ when prescribing orthotics to be fabricated by a podiatrist. The use of orthotics, including heel cups and plantar fascia support insoles, was found to be effective in alleviating pain from plantar fasciitis.
- In addition, it was shown that prefabricated insoles were not inferior to custom-made ones, giving patients without true biomechanical abnormalities, such as pes planus/cavus, a more economical option. (Rx,rx) However, as prefabricated insoles come in a myriad of designs, physicians should exercise caution when making generalizations.
Analgesia
- The use of nonsteroidal anti-inflammatory drugs (NSAIDs) to treat plantar fasciitis is a widespread practice that has been called into question, as plantar fasciitis is not an inflammatory process. This is supported by a recent study showing no significant difference in pain and disability scores in patients who were given NSAIDs compared to those who received a placebo. (rx) However, when combined with other treatment modalities, NSAIDs or simple analgesics may help to provide short-term pain relief. (rx)
Steroid Injection
- Localized steroid injections into the plantar fascia have been shown to provide effective short-term relief of plantar fascia pain for up to three months.(rx) There is, however, increased risk of plantar fat pad atrophy and plantar fascia rupture with repeated corticosteroid injections,(rx) and thus, repeated injections should be avoided if possible.(rx)
Platelet-Rich Plasma Injection
- Localized platelet-rich plasma injections have shown much promise and appear to be safe.(rx) However, this modality is currently not approved by the Ministry of Health, Singapore, for the treatment of plantar fasciitis.
Focal Extracorporeal Shockwave Therapy
- Patients with recalcitrant plantar fascia pain can be referred to hospitals that offer ultrasonography-guided focal extracorporeal shockwave therapy (SWT) as part of their sports medicine service. This treatment has been shown to be efficacious for patients with chronic plantar fasciitis that did not respond well to conservative treatment.(rx,rx) SWT is a noninvasive procedure that takes about ten minutes per treatment; the patient usually requires two treatments spaced one week apart for optimal efficacy.(rx,rx)
How Orthotics Help Relieve Plantar Fasciitis
- Orthotics are corrective foot devices. They are not the same as soft, spongy, rubber footbeds, gel heel cups etc. Gel and rubber footbeds may cushion the heels and feet, but they do not provide any biomechanical correction. In fact, the gel can do the opposite and make an incorrect walking pattern even more unstable!
- Orthotic insoles work by supporting the arches while re-aligning the ankles and lower legs. Most people’s arches look quite normal when sitting or even standing. However, when putting weight on the foot the arches lower, placing added tension on the plantar fascia, leading to inflammation at the heel bone. Orthotics support the arches, which reduces the tension and overwork of the plantar fascia, allowing the inflamed tissue to heal.
- Orthotics needn’t be expensive, custom-made devices. A comprehensive Heel Pain study by the American Orthopaedic Foot and Ankle Society found that by wearing standard orthotics and doing a number of daily exercises, 95% of patients experienced substantial, lasting relief from their heel pain symptoms.
Plantar Fasciitis Medical Treatments
Cortisone-Steroid Injections
- Cortisone is a powerful anti-inflammatory and when injected directly into the heel it will work almost immediately. Bear in mind, however, that the treatment does not address the root cause of the inflammation, and needs to be repeated every few months. Also note, these injections are quite painful, and most doctors today will consider other, less invasive treatment options first.
Acupuncture
- Electroacupuncture and standard acupuncture are used in the treatment of plantar fasciitis and other foot problems such as neuromas and nerve impingement, numbness in the toes etc. In some cases, there is nerve entrapment within the foot combined with referred pain from other areas of the body. Some research suggests that acupuncture can be effective in the treatment of heel pain.
Trigger-Point Massage
- A trigger point is an irritable knot in the muscle tissue. When pressed trigger points are very tender and can cause pain in that specific spot or elsewhere in the body (referred pain). The response to pushing into the knot is a muscle twitch.
- The foot contains 126 muscles, tendons, and ligaments, so there are plenty of ‘hiding places’ for trigger points. Trigger points in the calf muscles often refer pain directly to the bottom of the foot. Trigger point therapy of the lower leg and foot can, therefore, be successful in the treatment of plantar fasciitis.
Strassburg Sock and Night Splint
- The Strassburg Sock consists of a tubular fabric with two adjustable straps which extends from the toes to the lower leg. The aim is to keep tension on the plantar fascia ligament all night long, so no tightness occurs overnight and little or no pain is experienced in the morning. In combination with orthotic insoles and exercises, this device can be very effective indeed. In an independent study published in the Journal of Foot and Ankle Surgery found some significant improvement in 55% of the participants.
- A night splint is very similar to the Strassburg sock, serving the same purpose. However, this boot-type device is very uncomfortable to wear at night and very cumbersome, this is why most people prefer wearing a sock.
Surgical Treatment
- If the patient continues to have moderate to severe symptoms that do not respond to nonoperative treatment for more than 6–12 months, referral to an orthopedic surgeon for operative treatment may be required.
- Albert dropped by your clinic two weeks later to thank you for treating his pain with only the calf and plantar fascia-specific stretch you taught him. He had since revised his health pledge to include a regular exercise programme that combines stationary cycling and a slow jog. He will gradually work toward 150 minutes of moderate exercise a week and will postpone his half marathon pledge for another year. Surgery is considered only after 12 months of aggressive nonsurgical treatment.
Gastrocnemius Recession
- This is a surgical lengthening of the calf (gastrocnemius) muscles. Because tight calf muscles place increased stress on the plantar fascia, this procedure is useful for patients who still have difficulty flexing their feet, despite a year of calf stretches.
- In gastrocnemius recession, one of the two muscles that make up the calf is lengthened to increase the motion of the ankle. The procedure can be performed with a traditional, open incision or with a smaller incision and an endoscope, an instrument that contains a small camera. Your doctor will discuss the procedure that best meets your needs. Complication rates for gastrocnemius recession are low but can include nerve damage.
Plantar Fascia Release
- If you have a normal range of ankle motion and continued heel pain, your doctor may recommend a partial release procedure. During surgery, the plantar fascia ligament is partially cut to relieve tension in the tissue. If you have a large bone spur, it will be removed, as well. Although the surgery can be performed endoscopically, it is more difficult than with an open incision. In addition, endoscopy has a higher risk of nerve damage.
Endoscopic Plantar Fasciotomy (EPF)
- It is a form of surgery whereby two incisions are made around the heel and the ligament is being detached from the heel bone allowing the new ligament to develop in the same place. In some cases, the surgeon may decide to remove the heel spur itself, if present.
- Just like any type of surgery, Plantar Fascia surgery comes with certain risks and side effects. For example, the arch of the foot may drop and become weak. Wearing arch support after surgery is therefore recommended.
- Heel spur surgeries may also do some damage to veins and arteries of your foot that allow blood supply in the area. This will increase the time of recovery.
Study | Level of Evidence [rx] | Sport | No. of subjects | Clinical examination | Treatment plan | Outcomes |
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Suzue et al., 2014[rx] | IV | Soccer | 1 élite athlete (29 years old, male) | MRI showed hyperplasia of the plantar fascia insertion at the calcaneus. |
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After (i) no pain improvement was highlighted. After (ii) partial rupture of plantar fascia was assessed. After (iii) gradual repair of the ruptured fascia was observed and RTA 5 months after injury. |
James et al., 2010[rx] | IV | Australian football | 1 élite athlete | PF diagnosis |
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After (i) good pain relief during the game without any complication was assessed. After (ii) partial improvement in symptoms was assessed. |
Nguyen, 2010[rx] | IV | Run | 1 élite athlete (29 years old, male) | PF diagnosis after a progressive increase of pain for at least 10–12 months. |
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After (i) only pain reduction for 2–3 days was observed. After (ii) limited improvement in symptoms was assessed. After (iii) immediate pain relief was assessed and athlete returns to pre-injury level of running. |
Moretti et al., 2006[rx] | II | Run | 20 competitive level runners and 34 recreational joggers (ranging in age from 30–42 years). | Presence of chronic pain at the proximal insertion of the plantar fascia for at least 6 months, which failed to respond to conservative treatments (medical, physical therapy, local injection and orthotic devices). Presence of heel spur on the lateral X-ray view of the foot was assessed. |
4 treatment sessions, once weekly, of low-dose ESWT (2000 pulses being delivered at each session at an average of 0.04 mg/mm2). | Good/excellent results and persistent improvement lasting 24 months were evaluated with VAS. Good correlation with inflammatory signs was assessed. 50 patients were able to resume their athletic activity as high as before treatment; 4 patients were not able to resume athletic activities because of the persistence of symptoms. |
Rompe et al., 2003[rx] | II | Run | 45 recreational athletes (both sex, ranging in age from 32–61 years). | Presence of symptoms of PF for at least 12 months was assessed. Over a period of more than 6 months, at least 3 attempts of conservative treatment had failed to provide pain relief. | After 4 weeks of treatment wash-out, subjects were randomized into two treatment groups: (i) ESWT (n=22, 3 treatment sessions of 2100 shocks at 16 mJ/mm2 at 4 Hz, with 1-week interval); (ii) sham treatment group (n=23). | The primary outcome measures performed with VAS after 6 and 12 months follow-up revealed an improvement in pain on first walking in both groups, with a statistically significant difference between groups in favour of treatment group. The same result was highlighted for the secondary outcome measures. |
Saxena et al., 2012 [rx] | II | Not specified | 37 athletically active subjects (both sex, ranging in age from 22–72 years). | Patients had to have a clinical diagnosis of PF for more than 6 months, with prior treatment of at least 3 conservative modalities. All EPF patients had to have had a corticosteroid injection, custom orthoses and refrain from running/sport for minimum of 2 months. |
Subjects were divided into 3 groups: (i) ESWT (n=11, 3 treatment sessions of 4 Hz for 2000 shocks at .24 mJ/mm2, after a gradual ramp-up of 500 shocks starting at .1 mJ/mm2, every 7±3 days); (ii) pESWT group (n=14); (iii) EPF group (n=12). | Outcomes evaluation on VAS and RM highlighted a statistical improvement for both EPF and ESWT groups, with EPF group significantly better than both ESWT and pESWT groups. Athletes in ESWT group were able to RTA in a time ranging between immediate and 2 months after treatment, while the EPF group was able to RTA in an average of 2.8 months. |
Saxena et al., 2004[rx] | II | Run Basketball Cycling | 16 athletically active subjects (study group, both sex, ranging in age from 20–72 years); 10 nonathletic subjects (control group, both sex, ranging in age from 43–58 years). | Presence of symptoms of PF for a minimum of 12 months and conservative treatment for a minimum of 6 months (rest, physiotherapy, ice massage, steroid injection, night splint, cast-boot, and prescription foot orthosis. | All patients underwent to an uniportal EPF; a low, below-knee, removable cast-boot was used for a total of 4 weeks for post-operative patients, not weight bearing for the first 2 weeks was recommended. | Outcomes evaluation on MPFS revealed a statistically significant improvement for both groups, though the score increase for control group was less then study group. The mean RTA for study group was 2.7±0.7 months. The mean RTA was significantly longer in the control group with respect to study group. Complications were noted in both groups. |
Hansberger et al. 2015[rx] | IV | Cross country Track and field Lacrosse | 7 physically active subjects (4 cross country athletes, 2 track athletes, 1 lacrosse athlete, and 1 university employee; both sex; ranging in age from 18–40 years). | Subjects had: (i) pain or tenderness in the medial arch and at the insertion of the plantar fascia at the medial tubercle of the calcaneus; (ii) pain with walking or dorsiflexion of the toes, especially in the morning; (iii) plantar fascia pain was either acute (n=5) or chronic (n=3), unilateral or bilateral. | PRRT were assessed; a number of treatments ranging from 1 to 6. | A single session of PRRT resulted in an immediate statistically significant reduction of pain as revealed on NPRS. PRRT has also produced a statistical amelioration in the DPA and PSFS. The subjects who completed PRRT multiple sessions highlighted complete resolution of pain on NPRS. PRRT appeared to have long-lasting results for a majority of athletes without any continued intervention. |
PF: Plantar fasciitis; MRI: magnetic resonance imaging; RTA: return-to-activity; IC: ischaemic compression; PRRT: Primal Reflex Release Technique™; PRP: platelet-rich plasma; NPRS: numerical pain rating scale; DPA: disability in the physically active scale; PSFS: patient-specific functional scale; EPF: endoscopic plantar fasciotomy; ESWT: extracorporeal shock wave therapy; pESWT: placebo extracorporeal shock wave therapy; VAS: visual analog scores; RM: roles and Maudsley scorers; MPFS: modified plantar fascia score; n: numbers of subjects.
Prevention
There are certain things that you can do to try to prevent plantar fasciitis, especially if you have had it before. These include:
- Regularly changing training shoes used for running or walking.
- Wearing shoes with good cushioning in the heels and good arch support.
- Losing weight if you are overweight.
- Regularly stretching the plantar fascia and Achilles tendon, especially before exercise.
- Avoiding exercising on hard surfaces
Reference
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- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951039/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4853481/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3687890/
- https://www.ncbi.nlm.nih.gov/books/NBK431073/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5505577/
- https://www.ncbi.nlm.nih.gov/pubmed/21916393
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