If only surgery wasn’t such a pain in the…. knee!!

Liz, a 65 year old retired nurse, was diagnosed with knee osteoarthritis (OA) several years ago. Her GP subsequently prescribed a range of non-surgical and pharmaceutical interventions to treat her knee pain with limited success. Recently, she was referred to an orthopedic surgeon to evaluate the need for a total knee replacement (TKR). While TKR is successful for the majority of patients, recent evidence suggests that 20% of patients will suffer from chronic pain after TKR surgery [4,11].

Liz is a fictive person but she fits the characteristics of the 500,000 patients who undergo TKR surgery every year in the US[16]. With the expected growth in the elderly population and concomitant rise in sedentary lifestyle choices, the incidence of OA is predicted to increase [4,5] and the incidence of TKR surgery is expected to rise to 3.5 million by 2030 – in the US alone!

Recent scientific endeavors have tried to identify pre-surgical biomarkers to identify subgroups of patients with a high risk of developing chronic post-surgical pain. Three patient characteristics are commonly associated with an increased risk of developing chronic post surgical pain[10]:

  • Females
  • Patients with untreated depression
  • Higher pain intensities before surgery

In addition to these three common risk factors, increasing evidence suggests that the central nervous system may play role in the development of chronic post-surgical pain. The central nervous system can become hyper sensitive (also known as central sensitization) when exposed to pain over a long period of time[9]. Based on some of the recent work done at our group, this blog will provide insight into the link between pre-surgical central sensitization and chronic post-surgical pain.

Let’s begin with understanding pain: If you are a veteran reader of this blog, you already know that pain is influenced by many factors and the underlying mechanisms for how we experience pain are not completely understood. A simple quantitative measure of pain intensity is a 10 cm visual analogue scale (VAS), where 0 indicates no pain and 10 indicates unbearable pain, however, this pain measurement does not describe the characteristic of the pain and therefore leaves very limited options for treatment. Quantitative sensory testing (QST) is widely used in research to understand the underlying pain mechanisms in musculoskeletal pain disorders [1,2,8,12]. Three components of QST are often used in OA research namely pressure pain thresholds (PTTs), temporal summation of pain and conditioning pain modulation (CPM). Evidence of these components reflects central sensitization.

Central sensitization in knee OA: Patients with knee OA have decreased PPTs around the knee and at sites remote from the knee compared to healthy controls[1,2,8]. Patients with chronic musculoskeletal pain, such as OA and fibromyalgia, show increased temporal summation of pain compared with controls[1,2,8,15], which is an indication of up regulation of pain in the central nervous system and believed to be a component in the transition from acute to chronic pain[3]. Conditioning pain modulation (CPM), a measure for subjects ability to control and decrease ongoing pain, is impaired in patients with knee OA compared with controls[1,2,8] and believed to be correlated to the extent of widespread pain in patients.

How can we use central pain biomarkers?: Accumulating evidence suggests that abnormal pre-surgical central pain mechanisms could play a role in the development of chronic pain after surgery. Impaired pre-surgical CPM before thoracotomy[19] and abdominal[17] surgery has shown to be associated with an increased risk of chronic pain after surgery. A recent study showed that pre-surgical widespread hyperalgesia was associated with chronic pain in patients after total hip replacement surgery[18]. Recently, our group published a paper showing that patients who developed severe chronic post-surgical pain after TKR surgery had a five fold increased temporal summation of pain before surgery compared with patients who had a normal recovery[12].

So, why is this important for Liz? Recent studies have showed that administration of drugs (such as pregablin or duloxetine) that target central pain mechanisms can decrease central sensitization[13,14] and decrease the pre surgical pain intensity in patients with knee OA[6,7]. Decreasing the level of central sensitization before surgery could potentially decrease the risk of chronic pain after surgery. Our center is currently involved in several studies to investigate 1) the benefit of QST screening before surgery and 2) the effect of treatments to counter central sensitization. Our goal is to provide individual treatment for Liz and the growing population of patients with OA to decrease the risk of chronic pain after surgery.

About Kristian Kjær Petersen

Kristian_PetersenDr Petersen holds a biomedical engineering degree in drug and tissue technology and his PhD thesis was entitled “chronic pain after total knee replacement”. The basis of his research focuses on developing pain biomarkers to understand the underlying pain mechanisms in patients to provide better diagnosis leading to better treatments. Dr. Petersen currently holds a post doc position at the Center for Sensory-Motor Interaction (SMI), Aalborg, Denmark.


[1] Arendt‐Nielsen L, Eskehave TN, Egsgaard LL, Petersen KK, Graven‐Nielsen T, Hoeck HC, Simonsen O, Siebuhr AS, Karsdal M, Bay‐Jensen AC. Association Between Experimental Pain Biomarkers and Serologic Markers in Patients With Different Degrees of Painful Knee Osteoarthritis. Arthritis & Rheumatology 2014;66:3317-3326.

[2] Arendt-Nielsen L, Nie H, Laursen MB, Laursen BS, Madeleine P, Simonsen OH, Graven-Nielsen T. Sensitization in patients with painful knee osteoarthritis. Pain 2010;149:573-581.

[3] Arendt-Nielsen L, Fernández-de-Las-Penãs C, Graven-Nielsen T. Basic aspects of musculoskeletar pain: from acute to chronic pain. Journal of Manual and Manipulative Therapy 2011;19:186-193.

[4] Beswick AD, Wylde V, Gooberman-Hill R, Blom A, Dieppe P. What proportion of patients report long-term pain after total hip or knee replacement for osteoarthritis? A systematic review of prospective studies in unselected patients. BMJ Open 2012;2:e000435-2011-000435. Print 2012.

[5] Brown EC,3rd, Clarke HD, Scuderi GR. The painful total knee arthroplasty: diagnosis and management. Orthopedics 2006;29:129-36.

[6] Chappell AS, Desaiah D, Liu‐Seifert H, Zhang S, Skljarevski V, Belenkov Y, Brown JP. A Double‐blind, Randomized, Placebo‐controlled Study of the Efficacy and Safety of Duloxetine for the Treatment of Chronic Pain Due to Osteoarthritis of the Knee. Pain Practice 2011;11:33-41.

[7] Chappell AS, Ossanna MJ, Liu-Seifert H, Iyengar S, Skljarevski V, Li LC, Bennett RM, Collins H. Duloxetine, a centrally acting analgesic, in the treatment of patients with osteoarthritis knee pain: a 13-week, randomized, placebo-controlled trial. Pain 2009;146:253-260.

[8] Graven‐Nielsen T, Wodehouse T, Langford R, Arendt‐Nielsen L, Kidd B. Normalisation of widespread hyperesthesia and facilitated spatial summation of deep‐tissue pain in knee osteoarthritis patients after knee replacement. Arthritis & Rheumatism 2012;64:2907-2916.

[9] Graven-Nielsen T, Arendt-Nielsen L. Assessment of mechanisms in localized and widespread musculoskeletal pain. Nature Reviews Rheumatology 2010;6:599-606.

[10] Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. The Lancet 2006;367:1618-1625.

[11] Petersen KK, Simonsen O, Laursen MB, Nielsen TA, Rasmussen S, Arendt-Nielsen L. Chronic Postoperative Pain After Primary and Revision Total Knee Arthroplasty. Clin J Pain 2015;31:1-6.

[12] Petersen KK, Arendt-Nielsen L, Simonsen O, Wilder-Smith O, Laursen MB. Presurgical assessment of temporal summation of pain predicts the development of chronic postoperative pain 12 months after total knee replacement. Pain 2015;156:55-61.

[13] Phillips K, Clauw DJ. Central pain mechanisms in chronic pain states–maybe it is all in their head. Best Practice & Research Clinical Rheumatology 2011;25:141-154.

[14] Price DD, Mao J, Frenk H, Mayer DJ. The N-methyl-D-aspartate receptor antagonist dextromethorphan selectively reduces temporal summation of second pain in man. Pain 1994;59:165-174.

[15] Staud R, Cannon RC, Mauderli AP, Robinson ME, Price DD, Vierck Jr CJ. Temporal summation of pain from mechanical stimulation of muscle tissue in normal controls and subjects with fibromyalgia syndrome. Pain 2003;102:87-95.

[16] Steven K, Kevin O, Edmund L, Fionna M, Michael H. Projections of primary and revision hip and knee arthroplasty in the United States from 2005 to 2030. The Journal of Bone & Joint Surgery 2007;89:780-785.

[17] Wilder-Smith OH, Schreyer T, Scheffer GJ, Arendt-Nielsen L. Patients with chronic pain after abdominal surgery show less preoperative endogenous pain inhibition and more postoperative hyperalgesia: a pilot study. Journal of Pain and Palliative Care Pharmacotherapy 2010;24:119-128.

[18] Wylde V, Sayers A, Lenguerrand E, Gooberman-Hill R, Pyke M, Beswick AD, Dieppe P, Blom AW. Preoperative widespread pain sensitization and chronic pain after hip and knee replacement: a cohort analysis. Pain 2015;156:47.

[19] Yarnitsky D, Crispel Y, Eisenberg E, Granovsky Y, Ben-Nun A, Sprecher E, Best L, Granot M. Prediction of chronic post-operative pain: pre-operative DNIC testing identifies patients at risk. Pain 2008;138:22-28.


  1. Anton Harms says

    Thank you Kristian for your presentation; very interesting.

    When I began working in the Osteoarthritis Hip and Knee Service (OAHKS), an Orthopaedic screening clinic assessing OA knees six years ago, I had little idea of the fascinating clinical experience that was to unfold. In addition to the challenge of OA knee conservative management optimisation I slowly became aware of the wide range of knee arthroplasty outcomes and have considered the possibilities of reliably identifying those who may be at risk of a poor outcome.

    Knee arthroplasty is a life changeingly beneficial procedure for many people; and a life changingly tragic one for a few; I also regularly encounter people whom I believe would benefit from arthroplasty but they are fearful and do not pursue it as they know somebody who had a poor outcome.

    Painful osteoarthritic knees are a very heterogeneous lot;

    Some people describe pain only on weight bearing activity; no pain at rest, no nocturnal pain, not much pain on active or passive range of movement exam and minimal or no joint line tenderness; but they can only walk 100-200m before pain (usually medial knee) slows them.

    At perhaps the other end of the spectrum; many describe a constant background ache; often with a burning quality; worsened by weight bearing; pain at rest and disruptive of sleep; pain increases on change of position (sit to stand); all knee movement is painful and on palpation there is widespread tenderness; perhaps importantly many are fearful of moving and become less and less active.

    Many show clear signs of cortical ‘imprecision’

    I: Poor two point discrimination; I have often measured a TPD threshold of 70-100mm (Tash Stanton found the ‘normal’ pain free subjects had a medial and lateral knee TPD threshold of 25-35mm)

    II: Poorer Left/Right judgement accuracy and slower decision making speed.

    III: ‘lower proprioceptive acuity’; I have begun assessing what I call knee ‘microproprioception’ using a laser pointer attached to the lower shin to track a complex linear pattern on a wall a metre or so away.

    Many have hypoaesthesia to punctate and dynamic light touch stimulation of the skin overlying the medial and lateral knee; 10g monofilament or 40g pin (using a ‘Neuropen’ designed for assessment of diabetic neuropathy) and a few are hyperaesthetic (allodynic) to either punctate or dynamic LT (10g) or both; and to 40g punctate pin prick.

    Some describe ‘burning’ pain as the predominant sensation; some describe spontaneous pains in the knee, unrelated to movement; some describe formication or paraesthesia around the knee.

    Some have indications of significant inflammatory processes; ie improve with intra-articular corticosteroid injection or oral NSAIDS; but many do not.

    Some can control the pain with regular paracetamol and others cannot.

    Most have quadriceps weakness (varying from mild to considerable) assessed using a simple open chain ankle weight paradigm.

    I have a hand held pressure algometer but I have not routinely done the QST screening you describe in your paper; fingers are quicker!

    It will be very interesting to see where your important research leads.

    Many thanks

    Anton Harms

  2. Very interesting article, thanks Kristian. It has also been found that administration of appropriate medication very soon after a traumatic event reduces the potential development of post traumatic stress syndrome (PTSD).
    perhaps the same mechanism is involved.
    MrPhysio + Healesville Mark Quittner

    Kristian Kjær Petersen Reply:

    Hi Mark
    Thanks for reading and for your comment. Would you care to elaborate on which kind of medications you have administrated and if possible send me a copy of the paper?

    Kristian Petersen