Prophylactic oral ibuprofen or ibuprofen-codeine...

Prophylactic oral ibuprofen or ibuprofen-codeine versus placebo for postoperative pain after primary hip arthroplasty.

Dahl V, Raeder J, Drøsdal S, Wathne O, Brynildsrud J.Acta Anaesthesiol Scand. 1995 Apr;39(3):323-6.

-123 hofteprotese op. pasienter – spinal bupivakain anestesi-Postop. enkeltdose per os: ibuprofen 800 mg vs. ibuprofen m/60 mg kodein vs placebo-Observasjon i 5 timer

Resultater:-Placebo pas hadde mer smerte -Placebo pas fikk 45% mer opioid (ketobemidon) rescue-Ingen forskjell i kvalme, blødning, andre bivirkninger-Kodein ga ingen tillegsgevinst (eller ulempe)

Post-operative bleeding, hip arthroplasty:

Slappendel R et al. Eur J Anaesthesiol 2002:19:829-831

50 patients, total hip replacement, spinal anaesthesia, same surgeon:

•Pretreatment for 2 weeks with either placebo or ibuprofen 600 mg x 3

Ibuprofen (n=17) Placebo (n=19)

Blood loss

- during surgery 700 ± 367 416 ± 203 P<0.01

- after surgery 461 ± 312 380 ± 169 ns

- total 1161 ± 472 796 ± 337 P<0.05

Number transfusions 9 6

COX-2 HEMMERE VS NSAIDS:• ingen effekt på blodplater (dvs.

blødning)• sign.reduksjon i gastrointestinale sår• mindre allergi• sterkere reseptorbinding (lengre

durasjon)------------------------------

• MEN:– Risiko for nyre svikt – Risiko for hypertensjon / hjerte svikt


Dahl V, Raeder J, Drøsdal S, Wathne O, Brynildsrud J.Acta Anaesthesiol Scand. 1995 Apr;39(3):323-6.

-123 hofteprotese op. pasienter – spinal bupivakain anestesi-Postop. enkeltdose per os: ibuprofen 800 mg vs. ibuprofen m/60 mg kodein vs placebo-Observasjon i 5 timer

Resultater:-Placebo pas hadde mer smerte -Placebo pas fikk 45% mer opioid (ketobemidon) rescue-Ingen forskjell i kvalme, blødning, andre bivirkninger-Kodein ga ingen tillegsgevinst (eller ulempe)

TELEFON, 24 T POST.OP,% smerte(medium/mye), PARAC+CODEIN

TABL(nx10):

0 10 20 30 40 50 60

Cholec

Varic

Gangl

Dupuy

Knee

Ost.t

Ost.r

Anal

Hernia

ALL

P+C TABLPAIN

Ullevaal, data on file

Fj. osteosyn.

Osteo-tomi

Kne a.skopi

KODEIN (60mg) + PARACET.(800mg)ELLER

IBUPROFEN (800mg) x 3 HJEMME:

Ræder J, Steine S, Vatsgar T. Anesth Analg 2001:92:1470-2

• 104 pas, hernie/varice kir.; gen.anestesi• dobbel-blindt 3 dager hjemme

----------------------------• 10 pat denied participation due to distrust in codeine+paracet.• Identical analgesia in both groups• 20-30% more nausea with codeine+paracet. • More obstipation with codeine+paracet (23% no defec. for 3d)• More general satisfaction with Ibuprofen

Increased risk of chronic pain

• genetic disposal • pain at other site before surgery• female gender• depressive state• general anaesthesia* (vs. spinal)• nerve damage• re-operation• strong postoperative pain• radiation damage

Kehlet H et al. Lancet 2006:367:1618-25 and *Brandsborg B et al Anesthesiology 2007 106 1003 12

KODEIN (60mg) + PARACET.(800mg)ELLER

IBUPROFEN (800mg) x 3 HJEMME:

Ræder J, Steine S, Vatsgar T. Anesth Analg 2001:92:1470-2

• 104 pas, hernie/varice kir.; gen.anestesi• dobbel-blindt 3 dager hjemme

----------------------------• 10 pas nektet å delta, (tidl. kvalme eller dårlig effekt av

kodein+paracet.)• Identisk analgesi i begge grupper (hvile/provokasjon, dag/natt,

peak/mean)• 20-30% flere med kvalme i kodein+paracet. gruppen • Mere obstipasjon med kodein+paracet (23% uten defec. for 3d)• Mere general tifredshet med smertelindring med Ibuprofen

Acta Anaesthesiol Scand. 1995 Apr;39(3):323-6.


Dahl V, Raeder JC, Drøsdal S, Wathne O, Brynildsrud J.

The postoperative analgesic effect of ibuprofen was compared with a combination of ibuprofen and codeine versus placebo. The study was prospective, randomized, double blind with 123 consecutive hip arthroplasty operations. All the patients received oral diazepam as premedication and spinal anaesthesia with bupivacaine 5 mg/ml 3-4 ml. Postoperatively, when the spinal anaesthesia started to wear off, the patients were randomly assigned to one of three groups; the ibuprofen group (n = 48) received 800 mg of ibuprofen orally. The ibuprofen/codeine group (IC, n = 48) received 800 mg of ibuprofen combined with 60 mg of codeine. The placebo group (P, n = 25), received oral placebo medication. The patients were observed for the need of additional opioid (e.g. ketobemidone), pain score (verbal and VAS), bleeding and side effects for five hours. The patients in the placebo group (P) had significantly higher pain scores (P < 0.05) compared with the two other groups after 2 and 4 hours, with no significant differences after 1, 3 and 5 hours. The P group also received 45% more opioids (P < 0.001) compared with the two other groups during the same period. No significant differences in bleeding or side-effects were observed between the groups. There were no significant differences between the ibuprofen group and the ibuprofen/codeine group. We conclude that a prophylactic dose of 800 mg ibuprofen orally has an opioid sparing effect with a tendency of less pain experience during the first hours after hip arthroplasty.

NSAIDs og glukokortikoider til smertebehandling av

ortopedkirurgiske pasienter

PRO !Johan Ræder

Anestesiavd. / UiO Oslo Universitets Sykehus,

Avd. Ullevål, Oslo

mail: [email protected]

Hvorfor kan vi ikke bare “droppe” NSAIDs til disse pasientene?

1. Ortopediske pasienter har mye postoperativ smerte

1. Inadekvat smertelindring har uheldige konsekvenser- Subjektivt ubehag- Redusert opptrening, forsinket recovery- Mer kroniske smerter

3. Forbud mot NSAID fører til økt bruk av opioider- Opioide bivirkninger

NSAIDs og ortopedisk kirurgi?

Opioid ”problemer”• Toleranseutvikling• Hyperalgesi utvikling• Bivirkninger

– Kvalme, obstipasjon, avhengighet, sedasjon, kløe, søvnvansker– Respirasjonsdepresjon

• Individuelle variasjoner i reseptor (genetisk)• Variabel enteral absorbsjon• Mindre effektive ved bevegelsesindusert smerte• Immundepresjon (infeksjon? cancer?)

men.......• Tar ≈ ”all” smerte hvis bare dosen er høy nok• Bivirkningsterskel følger toleranse (unntak: obstipasjon)• Relativt rimelige

22 studier, 2 307 pasienter:

Signifikant reduksjon med NSAID vs placebo:-Kvalme: ↓ 12%-Oppkast: ↓ 32%-Sedasjon: ↓ 29%

Opioid ”problemer”Case 1:- Hofteprotese pasient som ligger utover ettermiddagen, dag 2

på PO: smerter, opiod, kvalm, trett Ikke postklar- Ketorolac iv: mindre smerte, redusert opioid, postklar

Case 2:- Ung (12 år) rotasjonsosteaotomi, som ligger utover

ettermiddagen, dag 2 på PO: smerter, opiod, kvalm, trett Ikke postklar

- Ketorolac iv: mindre smerte, redusert opioid, postklar

Case 3:- Pasient med kneprotese på post; mye vondt, paracetamol +

opioidrespirasjonsstans på post

- Videre behandling m/paracet+ NSAID

Pain as a factor complicating recovery and discharge after ambulatory surgery:

Pavlin J et al. Anesth Analg 2002:95:627-34

175 patients, mixed surgery, general anaesthesia, 0-3 h observation post-op.:

• 24% of patients delayed recovery unit stay due to pain• 42% less opioid need when NSAID (ketorolac) was used

NSAIDs ogBen –sene tilheling

Faktorer som påvirker bentilheling:

• Tobakks røyking• Ernæring• Alder• Diabetes mellitus• Reumatoid artrit• Osteoporose• Opptrening• Bevegelse/belastning• Cytostatika• Systemiske glukokortikoider• NSAID

PHOSFOLIPID

ARACHIDONIC ACID

LEUKOTRIENPROSTAGLANDIN

PROSTAGLANDIN

phosfolipase

Cox-IICyclo-oxygenaseCox-I

substrateactivator

VEVS HOMEOSTASEnyrerGI-mucosatrombocyter

NSAID og Ortopedi:

- Hva er problemet?

PHOSFOLIPID

ARACHIDONIC ACID


PROSTAGLANDIN

phosfolipase


substrateactivator

PARACETAMOL ?

smerteinflammasjonallergi?


smerteinflammasjon

CELLE traumeNSAID og Ortopedi:

- Hva er problemet?

PHOSFOLIPID

ARACHIDONIC ACID


PROSTAGLANDIN

phosfolipase


?

substrateactivator

CORTICOSTEROID

PARACETAMOL ?

NSAID COXIBsmerteinflammasjonallergi?


smerteinflammasjon

CELLE traume

EFFEKTER NSAID og Ortopedi:

- Hva er problemet?

PHOSFOLIPID

ARACHIDONIC ACID


PROSTAGLANDIN

phosfolipase


?

substrateactivator

CORTICOSTEROID

PARACETAMOL ?



smerteInflammasjonVevstilheling

CELLE traume

BIVIRKNINGERNSAID og Ortopedi:

- Hva er problemet?

FOSFOLIPID

ARAKIDONSYRE

LEUKOTRIENERPROSTAGLANDIN

PROSTAGLANDIN

fosfolipase

Cox-IICyclo-oksygenaseCox-I

substrataktivator

STEROID

PARACETAMOL

NSAIDsmerteInflammasjonallergi

VEVSHOMEOSTASEnyrerGI-slimhinnetrombocyter

smerteinflammasjontilheling ?

VEV (skade)

Cox-2 hemmer

BIVIRKNINGER ???

COX-1-knock-out mice have normal callus

formation and fracture healing

COX-2- knock-out mice have delayed callus

formation and fracture healing

Simon et al.: COX-2 function is essential for bone fracture healing. JBMR 17 (2002) 963 - 976

Prostaglandiner og bentilheling:- Øker osteoblast aktivitet- Reduserer osteoklast aktivitet

Cox – I hemming

Cox – II hemming

Indometacin (Indocid)

Ketorolac (Toradol)

Naproxen (Naprosyn)

Ibuprofen (Ibux, Brufen etc)

Diclofenac (Voltaren, Diklofenak)

Celecoxib (Celebra)

Parecoxib (Dynastat)

Rofecoxib (Vioxx))

Etoricoxib (Arcoxia)

Lumiracoxib ((Prexige))

Trombocyteffekt +

Trombocyteffekt ÷

Dyrestudier…..

Inhibition of fracture healing by indomethacin in rats.

Sudmann E, Dregelid E, Bessesen A, Mørland JEur J Clin Invest. 1979:9:333-9

-Indomethacin 2 mg/kg/d, 205 rotter, ikke-fikserte femurfrakturer, placebo kontroll

-En serie med 29 d behandling – en (to !) serie med 7 dager behandling –fulgt i 90-120 dager

Resultat / Konklusjon:

Forsinket tilheling, økt feilstilling og mer ustabil fraktur med behandling (begge serier)

7 dagers behandling – tilheling (stabil + kallus “bro” med kalk) etter 90 -120 dager:- 53% etter indomethacin- 68% etter placebo (P=0.03)

Negative effect of parecoxib on bone mineral during fracture healing in rats

Dimmen S, Nordsletten L, Engebretsen L, Steen H and Madsen JE Acta Orthopaedica 2008,79:3,438 — 444

-2 x 26 rotter med parecoxib 0,5 mg/kg intraperit. x 2, i 7 dager, start pre-op (fraktur)

- Bentetthet, 2, 3 og 6 uker;- Styrketesting v/ 6 uker

Resultat / Konklusion:

“Parecoxib given postoperatively for a week has a negative effecton mineralization during the early phase (week 2 and 3) of fracture healing”.



-2 x 26 rotter med parecoxib 0,5 mg/kg intraperit. x 2, i 7 dager, start pre-op (fraktur)- bentetthet, 2, 3 og 6 uker; styrketesting v/ 6 uker

Høy verdi er “best”




Interpretation:

- No mechanical differences were detected between the control and treatment groupsafter 6 weeks, but they may have been present earlier in the fracture healing process.(!)

- Our findings do, however, indicate that parecoxib given postoperatively for a week has a negative effect on mineralization during the early phase of fracture healing.





…. The mechanical strengthwas reduced after 6 weeks, but the study lacked sufficient statistical power to show the statistical significance of this finding……..

… We were able to confirm that parecoxib given for only a few days affects bone metabolism….*

* Reelt eller surrogat outcome?


Fluor in the treatment of osteoporosis.An overview of thirty years clinical research.

Dequeker J, Declerck KSchweiz Med Wochenschr. 1993 Nov 27;123(47):2228-34. Links

-Fluoride has a positive effect on axial bone density,

………. but the axial bone gain is not matched by similar changes in cortical bone

-In two controlled fluoride therapy studies the incidence of vertebral fractures decreased, while in two other studies it increased.

- Experience teaches that denser bones are not necessarily better bones.

Problemer med Dyr Menneske:

• Hva er ekvipotente doser?• Hva er sammenlignbar post-frakturfase og

behandlingslengde? (” alt går 2-3 ganger fortere hos rotte” ?)

• Hva er sammenlignbar ”post-fraktur” oppførsel?– Ro, hvile, fraktur immobilisering– Opptrening, fysioterapi

• Andre faktorer:– Biologisk alder, ernæring, bentetthet…..

• Statistisk styrke – etikk:– Reell non-union sjelden (rtg.logisk hyppig

relevans?)

Humane prospektive dobbeltblinde kliniske studier:

Scoliose kirurgi:- sensitiv modell for tilheling av frakturer i spongiøst vev

Peri-operative NSAIDs or coxibs in patients for posterior spinal fusion:

1 yr Non-union rate:

1Glassman et al, Spine 1998; 23: 834: 60mg loading + 30 mg x 4, for 3 days +/-

Reuben et al, Reg Anesth Pain Med 2001; 26 (Suppl. 1): 49

Ketorolac and spinal fusion:Does the perioperative use of ketorolac really inhibit spinal fusion?

Pradhan BB, Tatsumi RL, Gallina J, Kuhns CA, Wang JC, Dawson EGSpine 2008:33:2079-82

Piroxicam (20 mg)

and Colles fracture

P Adolphson et al. No effects of piroxicam on osteopenia and recovery after Colles' fracture. Arch Orthop Trauma Surg 1993 112: 127-130

Study: Randomised, double-blind trialPiroxicam 20 mg/Placebo daily for 8 weeks (n=42 women)in postmenopausal women

Results: Less pain in the NSAID-group compared to the placebo group

No differences or decrease in fracture healing

No difference in bone mineral density

Prophylaxis with

Indomethacin 100 mg(n = 134)

Control group without any prophylaxis

(n=44)

Early Loosening

0 1

Revision 0 0

NSAIDs/COXIBs and Total Hip ReplacementFollow up: 65 mths (60-71 mths)

Trnka et al.: Stable bony integration with and without short-term indomethacin prophylaxis. Arch Orthop Trauma Surg 119 (1999) 456-460

Prophylaxis with

Diclofenac 2x75 mg (n = 168)

Rofecoxib 1 x 25 mg (n=101)

Early Loosening

0 0

Revision 0 0

NSAIDs/COXIBs and Total Hip Replacement(Follow up: 6 mths – Zacher J data on file)

In our database of prospective studies with NSAIDs/COXIBs and THR there are no signs of compromising bony ingrowth of the implants

-Kneprotese kirurgi, 2 x 35 pas-50 mg rofecoxib 1d + 1 t preop + 5 dager, deretter 25 mg daglig i 8 dagervs placebo

------------------------

Fordeler (sign) m/rofecoxib:- Mindre smerte første uke- Mindre kvalme og søvnforstyrrelse- Bedre knefleksjon, mindre behov for fysioterapi etter 1 mnd

The effect of initiating a preventive multimodal analgesic regimen on long-term patient outcomes for outpatient anterior cruciate ligament reconstruction surgery.

Reuben SS, EkmanAnesth Analg. 2007;105:228-32.

- 200 korsbåndsopererte - alle fikk lokal an i ledd + kjøling v/kir avslutning- Alle fikk paracetamol 1g preop og deretter 1g x 4 i 14 dager-Randomisert til Celecoxib 400 mg preop + deretter 200 mg x 2 i 14 dagereller-Placebo

Resultat / Konklusjon v/ kontroll etter 6 mnd:Flere patellofemorale komplikasjoner m/ placebo (P=0.001):- anterior knee pain 15% vs 1%

- complex regional pain syndrome 7% vs 1% - flexion contractures 9% vs 2% - scar tissue requiring re-arthroscopy 8% vs 2%------------------------------------------------------------------------ Færre med forbedret aktivitetsnivå: 65% vs 84% - Færre klarte intens aktivitet (P < 0.02), og full sportslig aktivitet (P < 0.05).

Anesth Analg. 2008;106:1258-64

A prospective Randomized Trial on the Role of Perioperative Celecoxib Administration for Total Knee Artroplasty: Improving Clinical Outcome

Reuben SS, Buvenandran A, Katz B, Kroin JS.Anesth Analg 2008:106:1258-64

- 200 pasienter, alle m/ pasient kontrollert epidural analgesi post.op. i 2 døgn- Celecoxib: 100 mg x 2 uken før, 400 mg rett før, 200 mg x 2 i 10 dager etterpåvs placebo

Resultat - Fordeler (sign) m/ Celecoxib:-Mindre behov for epidural analgesi-Mindre behov for oxykodon hjemme-Bedre bøyefunksjon første 3 dager-Raskere full felksjon (90°)-Mindre kvalme, oppkast, kløe postop

-Bedre knefunksjon v/ ett års kontroll

A prospective Randomized Trial on the Role of Perioperative Celecoxib Administration for Total Knee Artroplasty: Improving Clinical Outcome

Reuben SS, Buvenandran A, Katz B, Kroin JS.Anesth Analg 2008:106:1258-64

- 200 pasienter, alle m/ pasient kontrollert epidural analgesi post.op. i 2 døgn- Celecoxib: 100 mg x 2 uken før, 400 mg rett før, 200 mg x 2 i 10 dager etterpåvs placebo

Resultat - Fordeler (sign) m/ Celecoxib:-Mindre behov for epidural analgesi-Mindre behov for oxykodon hjemme-Bedre bøyefunksjon første 3 dager-Raskere full fleksjon (90°)-Mindre kvalme, oppkast, kløe postop

-Bedre knefunksjon v/ ett års kontroll

Hva gjør vi ??

Prospect projecthttp://www.postoppain.org

- Procedure specific evidence based recommendations on postoperative pain management

- 4 surgeons (Kehlet at al) + 6 anasthesiologists (Rawal et al.)

- Evidence based Cochrane approach (Grade A-D evidence)

• Abdominal hysterctomy• Herniorraphy• Laparoscopic cholecystect• Open colonic resection• Thoracotomy• Total hip arthroplasty• Total knee arthroplasty

Total Knee Arthroplastyhttp://www.postoppain.org

Postoperative:Systemic analgesia:• Conventional NSAID/COX-2-selective inhibitors (Grade A) + strong opioids (Grade A), titrated to effect (for high intensity pain) +

paracetamol (Grade B)• Conventional NSAID/COX-2-selective inhibitors (Grade A) +/- weak opioids (Grade B), titrated to effect (for moderate or low intensity pain) +

paracetamol (Grade B)Regional analgesia:

• - Femoral nerve block (Grade A)• · Continuous passive motion (for reasons other than analgesia) (Grade A)· Intensive rehabilitation (for reasons other than analgesia) (Grade D)

Total Hip ArthroplastyPostoperativeSystemic analgesia

• COX-2-selective inhibitors (grade A) or conventional NSAIDs (grade B) (depending on patient risk factors) – in combination with strong or

weak opioids, as required for pain intensity

• Strong opioids (grade B) – in combination with non-opioid analgesia for high-intensity pain, preferably administered intravenously by patient-

controlled analgesia (grade B) or fixed-interval injection (grade D)

• Weak opioids for moderate- or low-intensity pain (grade A) if conventional NSAIDs or COX-2-selective inhibitors are not sufficient or are

contraindicated

• Paracetamol (grade A) – for all pain intensities in combination with conventional NSAIDs or COX-2-selective inhibitors (with or without weak

opioids)

Prof. Alain Borgeat, Professor/ChairmanBalgrist University Orthopedic Hospital, ZurichEditor, Anesthesiology:

” We use NSAID or coxib to all postoperative orthopedic patients for one week, only exception is rotator-cuff surgery”

Prosedyre for ikke-opioid postoperativ smertelindring, ortopediske pasienter:

Oslo Universitets Sykehus – Anestesi /Ortopedisk kir avd Ullevål– Sept-08

Ortopedisk betingede kontraindikasjoner er mye basert pådyrestudier og eksperimentelle studier; ut fra ”føre var prinsippet”, i en situasjon hvor det er lite kliniske studier foreløpig som viser skadelige effekter.

Hos pasienter hvor annen god smertelinding er vanskelig å få til eller er utilstrekkelig, kan på individuelt grunnlag ortoped og anestesilege i samråd forordne disse midlene utover relative kontraindikasjoner for en kort periode.

Spesifikke kontraindikasjoner: ??

Takk !

mail: [email protected].

no

[email protected]

Da er velalt greit?

Prosedyre for ikke-opioid postoperativ smertelindring, ortopediske pasienter:

Ullevål Universitets Sykehus – Anestesi /Ortopedisk kir avd – Sept-08

Ortopedisk betingede kontraindikasjoner er mye basert på dyrestudier og eksperimentelle studier; ut fra ”føre var prinsippet”, i en situasjon hvor det er lite kliniske studier foreløpig som viser skadelige effekter.

Hos pasienter hvor annen god smertelinding er vanskelig å få til eller er utilstrekkelig, kan på individuelt grunnlag ortoped og anestesilege i samråd forordne disse midlene utover relative kontraindikasjoner for en kort periode.

Spesifikke kontraindikasjoner:

- Skaftfrakturer i: humerus, radius, ulna, femur, tibia, fibula og metatars. Det gjelder kun frakturer i skaftet, dvs. diafysen, og ikke f.eks. distale radiusfrakturer og ankelfrakturer.

- Frakturer og seneskader i hånden.

- Stressfrakturer

- Avstivning av ryggraden (alle typer)

-Osteotomi og artrodese (alle typer)

- Fractura colli femoris operert med osteosyntese.

- Operasjoner for pseudartrose

- Senetilheling og sene-ben tilheling. Inkluderer rotatorcuffsuturer og korsbåndsoperasjoner med rene senegraft.

- Implantater som krever ben-innvekst (eks. usementert hofteprotese)

- Andre frakturer og situasjoner med dårlige tilhelingsforhold for ortopediske strukturer eller hud, operatør skal da si spesielt ifra.

Anesth Analg. 2007 Jul;105(1):19-20.

Non-steroidal anti-inflammatory drugs, cyclooxygenase-2 and the bone healing process.

Vuolteenaho K, Moilanen T, Moilanen E.Basic Clin Pharmacol Toxicol. 2008 Jan;102(1):10-4.

-Results of fracture healing studies in animals treated with NSAIDs or in mice lacking COX-2 gene show that inhibition or deficiency of COX-2 impairs the bone healing process.

-The limited clinical data also support the assumption that inhibition of COX-2 by non-selective or COX-2-selective NSAIDs delays fracture healing.

-However, the clinical significance of the effect in various patient groups needs to be carefully assessed and further investigations are needed to characterize the patients at the highest risk for NSAID-induced delayed fracture healing and its complications.

- In the meantime, use of NSAIDs in fracture patients should be cautious, keeping in mind the benefits of pain relief and inhibition of ectopic bone formation on one hand, and the risks of non-union and retarded union on the other hand.

December 2007

Schweiz Med Wochenschr. 1993 Nov 27;123(47):2228-34. LinksFluor in the treatment of osteoporosis. An overview of thirty years clinical research.Dequeker J, Declerck K.Department of Rheumatology and Arthritis, K. U. Leuven, U. Z. Pellenberg, Belgium.

t has long been known that fluoride "hardens" mineralized tissues. Fluoride ingestion through drinking water in areas naturally rich in fluoride leads to osteosclerosis, known as endemic fluorosis. The first suggestion that fluoride be used in the treatment of osteoporosis was made in 1964. However, despite 30 years of research, the treatment remains controversial. Fluoride has a dual effect on osteoblasts. On the one hand, it increases the birthrate of osteoblasts at tissue level by a mitogenic effect on precursors of osteoblasts, while on the other hand it has a toxic effect on the individual cell with mineralization impairment and reduced apposition rate resembling osteomalacia. Fluoride has a positive effect on axial bone density, but the axial bone gain is not matched by similar changes in cortical bone. Furthermore, approximately one third of patients are non-responders. The effect of the addition of fluoride to the drinking water on fracture rate is not clear. It probably only has a small relative impact on total hip fracture rates. In two controlled fluoride therapy studies the incidence of vertebral fractures decreased, while in two other studies it increased.Experience teaches that denser bones are not necessarily better bones. The major side effects of fluor therapy are skeletal fluorosis, gastrointestinal intolerance, and painful lower extremity syndrome. Fluoride is the single most effective agent for increasing axial bone volume in the osteoporotic skeleton; however, its therapeutic window is narrow. The best candidates for fluoride therapy are patients with axial osteoporosis but with good peripheral bone density. They should have a good renal function and vitamin D status.(ABSTRACT TRUNCATED AT 250 WORDS)

IKKE-PLANLAGT INNLEGGELSE OG RE-INNLEGGELSE (Ullevaal, 2411 patients):

Grøgaard B, Aasbøe V, Ræder J. Tidsskr DNLF 1996:116:742-5

INNLEGGELSE: 1.5% (35 pasienter)• kirurgi 37%• anestesi 29% (inkl. kvalme)• smerte 20%• sosiale års. 14%



INNLEGGELSE: 1.5% (35 pasienter)• kirurgi 37%• anestesi 29% (inkl. kvalme)• smerte 20%• sosiale års. 14%

RE-INNLEGGELSE*: 1.0% (24 pasienter)

• kirurgi 88%• smerte 12%

IN-HOSPITAL RECOVERY PERIODE % SMERTE (medium/mye), % I.V.OPIOID:

0 20 40 60 80

Cholec

Varic

Gangl

Dupuy

Knee

Ost.t

Ost.r

Anal

Hernia

ALL

OPIOID I.V.PAIN

Ullevaal, data on file

Konsekvenser av smerte:• Ubehag for pasienten

• Adrenerg respons – Kardiovaskulært: BT stiger, Hjertefrekvens øker– Redusert sirkulasjon (=funksjon) i nyre, tarm

• Generell stress respons– Katabolisme

• Immobilisering

• Sekundære effekter: fysiske, psykiske, sosiale

• Økte sekundær kostnader – Medikamenter, behandling, innlegging, sykemelding osv

Hvordan kan vi dempe smerten med medikamenter?

• Lokal anestesi• Paracetamol• NSAID• Coxib (cox-II spesifikke NSAID)• Corticosteroider• Spesielle Calcium blokkere (nevrogen smerte)• Antikonvulsiva (nevrogen smerte)• Opioider iv / (im) / oralt• Epidural analgesi• (ketamin)

PHOSFOLIPID

ARACHIDONIC ACID


phosfolipase

Cyclo-oxygenase

NSAIDsmerteinflammasjonallergi?

VEVS HOMEOSTASEnyrerGI-mucosatrombocytersmerteinflammasjon

CELLE traume

PHOSFOLIPID

ARACHIDONIC ACID


PROSTAGLANDIN

phosfolipase


?

substrateactivator

CORTICOSTEROID

PARACETAMOL ?



smerteinflammasjon

CELLE traume

FOSFOLIPID

ARAKIDONSYRE

LEUKOTRIENERPROSTAGLANDIN

PROSTAGLANDIN

fosfolipase

Cox-IICyclo-oksygenaseCox-I

substrataktivator

STEROID

PARACETAMOL

NSAIDsmerteinflammasjon VEVSHOMEOSTASE

nyrerGI-slimhinnetrombocyter

smerteinflammasjontilheling ?

VEV (skade)

Cox-2 hemmer

COX-2 Upregulation Following Unilateral Hind-paw Inflammation

Goppelt-Struebe. Recent advances in prostaglandin, and leukotriene research. Plenum Press, NY. 1998, pp 213-216.

Glukokortikosteroider ??

(mean ± SD) Group P(n=40) Group B(n=38)

VAS 3 h: 32 ± 23 19 ± 17 **VAS 4 h: 28 ± 24 15 ± 18 *

Verbal Pain Score, 4-24 h post.op (0-3): 1.9 ±1.0 1.2 ±0.1 ***

Nausea or vomiting 5-24 h (%): 38 % 11 % **

Satisfaction, 24 h (bad/medium/good): 9/9/22 1/5/30 **

* P<0.05, ** P<0.01, *** P< 0.001

Aasbø V, Ræder JC, Grøgaard B. Anesth Analg 1998:87:319-23

BETAMETHASONE 12 mg i.m. (B) vs. PLACEBO (P):(hemorrhoidectomy or big toe osteocynthesis)

Adding dexamethasone 16 mg to paracetamol and rofecoxib ?

Anesth Analg. 2007:105:481-6

Efficacy and safety of steroid use for postoperative pain relief: ReviewSalerno A, Hermann R. J Bone Joint Surg Am 2006:88:1361-72

• Strong, grade A-evidence supporting the use of corticosteroids in multimodal analgesia, to minimize opioid doses and side-effects

• Optimal mode, dose and timing of administration remains unclear

• No serious side-effects documented

Side-effects with short-term use: Metanalyses

Sauerland S et al. Drug Saf 2000:

51 studies, 15 – 30 mg/kg methylprednisolone:

• No significant increase in complications• Tendency of more gastrointestinal

bleeding and wound complications• Significantly less pulmonary complications

in trauma patients

Post-operative recovery: Day-surgery patients’ preferencesJenkins K. et al. Br J Anaesth 2001:86:272-4

355 pas: Hva vil du helst unngå av 10 mulige post.op plager?

1) Smerte2) Hoste/ubehag v/ rør i halsen3) Kvalme / oppkast

Clin Orthop Relat Res. 2003;(416):27-36. Predicting total knee replacement pain: a prospective, observational study.

Brander VA, Stulberg SD, Adams AD, Harden RN, Bruehl S, Stanos SP, Houle T.Northwestern University, Orthopedic Institute, Memorial Hospital Joint Reconstruction and Implant Service, and Department of Physical Medicine and Rehabilitation, Feinberg School of Medicine, Chicago, IL 60611, USA. [email protected]

To describe the natural history of pain after total knee arthroplasty and to identify factors predicting excessive postoperative pain, we used a prospective, observational study assessing clinical and radiographic variables preoperatively and at 1, 3, 6, and 12 months after knee replacement. Data sources included the visual analog pain scale and other measures of patient health, psychologic state, and component reliability. Regression analyses were conducted to identify specific factors predictive of postoperative pain, controlling for inequality of variables, and confirmed using regression diagnostics. For 116 patients (149 knees; mean age, 66 years; 55.2% women), significant pain was reported by 72.3%, 44.4%, 22.6%, 18.4%, and 13.1%, respectively. No intergroup differences existed for anesthesia, weight, age, or gender. Patients with greater preoperative pain had more postoperative pain, used more home therapy, and postoperative manipulations. Preoperative depression and anxiety were associated with heightened pain at 1 year. Pain after knee replacement resolves quickly, declining to approximately (1/2) by 3 months. However, one in eight patients report moderate to severe pain 1 year after surgery despite an absence of clinical or radiographic abnormalities. Development of office-based preoperative screening tools and interventions for these patients may reduce postoperative costs and improve patient-perceived outcomes.

Etoricoxib – MEDAL study (American Heart – nov 06, Lancet 13/11-06)

• Prospective study on confirmed trombotic cardiovascular events• Etoricoxib (60 or 90 mg) versus Diclofenac (3x50 mg) daily• Mean duration of treatment 9 months (n=7100), 20 months (n= 27

600)• Allowed for: low-dose ASA, gastroprotection, previous CV disease• Significant findings:

– ≈ identical incidence of trombotic cardiovascular event (etoricoxib 5% less)

– More discontinuation due to hypertension with etoricoxib– More discontinuation due to edema and more cases of heart failure with

etoricoxib 90 mg – More discontinuation due to gastrointestinal events and/or hepatic

events with diclofenac

• Diclofenac is a cox-II inhibitor (partial) too !!So what?

J Bone Miner Res. 2000 Jun;15(6):993-1000. LUse of oral corticosteroids and risk of fractures.Van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C.Procter & Gamble Pharmaceuticals, Staines, UK.

Treatment with oral corticosteroids is known to decrease bone density but there are few data on the attendant risk of fracture and on the reversibility of this risk after cessation of therapy. A retrospective cohort study was conducted in a general medical practice setting in the United Kingdom (using data from the General Practice Research Database [GPRD]). For each oral corticosteroid user aged 18 years or older, a control patient was selected randomly, who was matched by age, sex, and medical practice. The study comprised 244,235 oral corticosteroid users and 244,235 controls. The average age was 57.1 years in the oral corticosteroid cohort and 56.9 years in the control cohort. In both cohorts 58.6% were female. The most frequent indication for treatment was respiratory disease (40%). The relative rate of nonvertebral fracture during oral corticosteroid treatment was 1.33 (95% confidence interval [CI], 1.29-1.38), that of hip fracture 1.61 (1.47-1.76), that of forearm fracture 1.09 (1.01-1.17), and that of vertebral fracture 2.60 (2.31-2.92). A dose dependence of fracture risk was observed. With a standardized daily dose of less than 2.5 mg prednisolone, hip fracture risk was 0.99 (0.82-1.20) relative to control, rising to 1.77 (1.55-2.02) at daily doses of 2.5-7.5 mg, and 2.27 (1.94-2.66) at doses of 7.5 mg or greater. For vertebral fracture, the relative rates were 1.55 (1.20-2.01), 2.59 (2.16-3.10), and 5.18 (4.25-6.31), respectively. All fracture risks declined toward baseline rapidly after cessation of oral corticosteroid treatment.

These results quantify the increased fracture risk during oral corticosteroid therapy, with greater effects on the hip and spine than forearm. They also suggest a rapid offset of this increased fracture risk on cessation of therapy, which has implications for the use of preventative agents against bone loss in patients at highest risk.

Etoricoxib – MEDAL study (American Heart – nov 06, Lancet 13/11-06)

• Prospective study on confirmed trombotic cardiovascular events• Etoricoxib (60 or 90 mg) versus Diclofenac (3x50 mg) daily• Mean duration of treatment 9 months (n=7100), 20 months (n= 27

600)• Allowed for: low-dose ASA, gastroprotection, previous CV disease• Significant findings:

– ≈ identical incidence of trombotic cardiovascular event (etoricoxib 5% less)

– More discontinuation due to hypertension with etoricoxib– More discontinuation due to edema and more cases of heart failure with

etoricoxib 90 mg – More discontinuation due to gastrointestinal events and/or hepatic

events with diclofenac

• Diclofenac is a cox-II inhibitor (partial) too !!So what?

MEDAL - konklusjoner• Samme incidens av trombotiske cardiovaskulære hendelser• Samme incidens av alvorlige GI-ulcer

• Mer GI ulcer og seponering grunnet GI problem m/diclofenac• Mer leverenzymstigning med diclofenac

• Mer seponering grunnet hjertesvikt, hypertoni og ødem med etoricoxib

Bone. 2000 Oct;27(4):563-8. Use of nonsteroidal anti-inflammatory drugs and risk of fractures.van Staa TP, Leufkens HG, Cooper C.Department of Pharmacoepidemiology and Pharmacotherapy, University of Utrecht, Utrecht, The Netherlands.

In animal models, prostaglandin synthesis has been found to mediate bone metabolism. Nonsteroidal anti-inflammatory drugs (NSAIDs), given their inhibitory effects of prostaglandin synthesis, may play a role in the prevention of osteoporosis. The primary objective of this study is to describe and quantify the fracture risks of patients exposed to NSAIDs in a representative general medical practice setting. A retrospective cohort study was conducted in a general medical practice setting in the UK (using data from the General Practice Research Database). Regular NSAID users (who received three or more NSAID prescriptions), aged 18 years or older, were compared with matched control patients and incidental NSAID users.

•The study comprised 214,577 regular NSAID users, 286,850 incidental NSAID users, and 214,577 control patients. •The relative rate of nonvertebral fractures during regular NSAID treatment compared with control was 1.47 (95% confidence interval [CI] 1.42-1. 52) and that of hip fracture 1.08 (0.98-1.19).• No differences in nonvertebral fractures were found between the regular and incidental NSAID users (RR = 1.04; 95% CI 0.99-1.09). The rate of nonvertebral fractures among users of diclofenac (RR = 1.00; 95% CI 0.93-1.08) and naproxen (RR = 0.91; 95% CI 0.82-1.00) was similar to that of ibuprofen.

The results of this study are not supportive of clinically significant effects of NSAIDs on bone metabolism.

Acta Anaesthesiol Scand. 1995 Apr;39(3):323-6.


Dahl V, Raeder JC, Drøsdal S, Wathne O, Brynildsrud J.

The postoperative analgesic effect of ibuprofen was compared with a combination of ibuprofen and codeine versus placebo. The study was prospective, randomized, double blind with 123 consecutive hip arthroplasty operations. All the patients received oral diazepam as premedication and spinal anaesthesia with bupivacaine 5 mg/ml 3-4 ml. Postoperatively, when the spinal anaesthesia started to wear off, the patients were randomly assigned to one of three groups; the ibuprofen group (n = 48) received 800 mg of ibuprofen orally. The ibuprofen/codeine group (IC, n = 48) received 800 mg of ibuprofen combined with 60 mg of codeine. The placebo group (P, n = 25), received oral placebo medication. The patients were observed for the need of additional opioid (e.g. ketobemidone), pain score (verbal and VAS), bleeding and side effects for five hours. The patients in the placebo group (P) had significantly higher pain scores (P < 0.05) compared with the two other groups after 2 and 4 hours, with no significant differences after 1, 3 and 5 hours. The P group also received 45% more opioids (P < 0.001) compared with the two other groups during the same period. No significant differences in bleeding or side-effects were observed between the groups. There were no significant differences between the ibuprofen group and the ibuprofen/codeine group. We conclude that a prophylactic dose of 800 mg ibuprofen orally has an opioid sparing effect with a tendency of less pain experience during the first hours after hip arthroplasty.

Anesth Analg. 2007;105:228-32. The effect of initiating a preventive multimodal analgesic regimen on long-term patient outcomes for outpatient anterior cruciate ligament reconstruction surgery.Reuben SS, Ekman EF.Department of Anesthesiology, Baystate Medical Center, Springfield, MA 01199, USA. [email protected]

BACKGROUND: Unrelieved postoperative pain may impair rehabilitation, delay recovery, and result in poor outcomes. Preventive multimodal analgesic techniques may improve long-term outcome after surgery. METHODS: We randomized 200 consecutive patients to receive acetaminophen 1000 mg and either celecoxib 400 mg or placebo 1-2 h before anterior cruciate ligament surgery. All patients received intraarticular analgesics and had an external cooling system applied to the operative knee. After discharge patients were instructed to take acetaminophen 1000 mg every 6 h and either celecoxib 200 mg every 12 h or matching placebo for the first 14 days postoperatively. All patients were enrolled in an accelerated rehabilitation program. Six months postoperatively, the level of activity was assessed, as was the presence of patellofemoral complications including: anterior knee pain, flexion contracture, quadriceps weakness, and complex regional pain syndrome. RESULTS: More patients in the control group developed patellofemoral complications compared to the celecoxib group (P = 0.001) including anterior knee pain (14/96; 15%) vs (4/95; 1%), complex regional pain syndrome (7/96; 7%) vs (1/95; 1%), flexion contractures (9/96; 9%) vs (2/95; 2%), and scar tissue requiring re-arthroscopy (8/96; 8%) vs (2/95; 2%) respectively. More patients in the celecoxib group returned to a higher activity level (84% vs 65%) (P < 0.01), were able to participate at a more intense level (P < 0.02), and return to full sports activity (P < 0.05). CONCLUSIONS: The administration of celecoxib as a component of a preventive multimodal analgesic technique for anterior cruciate ligament reconstruction reduces long-term patellofemoral complications and increases the likelihood of returning to a preinjury level of activity.



-2 x 26 rotter med parecoxib 0,5 mg/kg intraperit. x 2, i 7 dager, start pre-op (fraktur)- bentetthet, 3-3 og 6 uker; styrketesting v/ 6 uker

……The mechanical strengthwas reduced after 6 weeks, but the study lacked sufficient statistical power to show the statisticalsignificance of this finding……..

… We were able to confirm that parecoxib given for only a few days affects bone metabolism.

…..Two editorials have asserted that these drugs should be avoided during the period of bone healing because they may possibly lead to delayedfracture union (Aspenberg 2002, Einhorn 2002).Our findings support this view.

Author Animal Dose of drug Duration

Bo et al. 1976 Rats (femur) Indometacin 2 mg/kg/d 24 days

Altman et al. 1995

Rats (femur) Indometacin 1 mg/kg/dIbuprofen 30 mg/kg/d

12 weeks

Simon et al. 2002

Rats (femur) Indometacin 1 mg/kg/d Celecoxib 4 mg/kg/d Rofecoxib 3 mg/kg/d

8 weeks

Bo et al.: Effect of indomethacin on fracture healing in rats. Acta Orthop. Scand. 47 (1976) 588-599Altman et al.: Effect of NSAIDs on fracture healing: a laboratory study in rats. J. Orthop. Trauma 9 (1995) 392-400Simon et al.: COX-2 function is essential for bone fracture healing. JBMR 17 (2002) 963 - 976

Overall Result: Delayed bone healing

Flere dyrestudier………

Zacher J. et al.: Prevention of periarticular ossification (PAO) after total hip replacement (THR) with rofecoxib 25 mg. Abstract EULAR 2001, Prag

PAO Without

prophylaxis

n=317 n= 50

Prophylaxis with Diclofenac (literature)

n=54 n=55 n=57

Prophylaxis with Diclofenac 2x75 mg

(own data, n=168)

Rofecoxib 1 x 25 mg

n=101

Brooker 0 36,3 40,0 88,9 63,6 76,6 83,3 77,7

Brooker I 27,4 16,0 9,3 30,9 20,8 11,9 22,3

Brooker II 13,9 18,0 1,8 5,5 2,6 4,8 0

Brooker III 14,8 22,0 0 0 0 0 0

Brooker IV 7,6 4,0 0 0 0 0 0

Ektopisk bendannelse v/ hofteprotese:hemmes av NSAID/cox-II*

hemmer

*behandling over flere uker-mnd

Heterotopic ossification prophylaxis with indomethacin increases the risk of long-bone nonunion.

Burd TA, Hughes TA, Anglen JO. Bone Joint Surg Br. 2003;85:700-5

- Pasienter med op. acetabulær + skaftfraktur av femur- Stråleterapi (n=38) eller indometacin (n= 38) 25 mg x 3 I 6 uker mot ektopisk bendannelse

Resultat / Konklusjon:-26% non-union med indomethacin-7% non-union med stråleterapi

P= 0.004

Patients with concurrent fractures of the acetabulum and long bones who receive indomethacin have a significantly greater risk of nonunion of the fractures of the long bones when compared with those who receive XRT or no prophylaxis.

Heterotopic ossification prophylaxis with indomethacin increases the risk of long-bone nonunion.

Burd TA, Hughes TA, Anglen JO. Bone Joint Surg Br. 2003;85:700-5

- Pasienter med op. acetabulær + skaftfraktur av femur- Stråleterapi (n=38) eller indometacin (n= 38) 25 mg x 3 I 6 uker mot ektopisk bendannelse

Resultat / Konklusjon:-26% non-union med indomethacin-7% non-union med stråleterapi

P= 0.004

“Patients with concurrent fractures of the acetabulum and long bones who receive indomethacin have a significantly greater risk of nonunion of the fractures of the long bones when compared with those who receive XRT or no prophylaxis.”

Use of oral corticosteroids and risk of fractures.

Van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper CJ Bone Miner Res. 2000 Jun;15(6):993-1000. L

- Retrospektiv cohort study, UK, 244,235 oral corticosteroid brukere og 244,235 kontroller- 57 år gj.snitt alder, 59% kvinner, 40% fikk steroid for luftveis/lunge sykdom

Resultat:Relativ rate frakturer hos steroid brukere vs ikke-steroid brukere:-Ikke-vertebrale frakturer: 1.33 (95% confidence interval [CI], 1.29-1.38), -Hoftefraktur: 1.61 (1.47-1.76)-Underarmsbrudd 1.09 (1.01-1.17)- Vertebra frakturer: 2.60 (2.31-2.92).

Doseavhengig økning I fraktur risk: Hoftefraktur Vertebra fraktur<2.5 mg prednisolon per dag 0.99 (0.82-1.20) 1.55 (1.20-2.01)

2.5-7.5 mg prednisolon per dag 1.77 (1.55-2.02) 2.59 (2.16-3.10)> 7.5 mg prednisolon per dag 2.27 (1.94-2.66) 5.18 (4.25-6.31

All fraktur risiko sank til baseline i løpet av 1-4 år etter seponering av prednisolon

Use of nonsteroidal anti-inflammatory drugs and risk of fractures.

van Staa TP, Leukens HG, Cooper CBone. 2000 Oct;27(4):563-8.

- Retrospektiv cohort study, UK, 214 577 faste NSAID brukere, 286 850 uregelmessig brukere og 214 577 kontroller- 51 år gj.snitt alder, 62% kvinner, 20% fikk NSAID for ryggsmerter

Resultat:Ikke-vertebrale frakturer, fast NSAID vs kontroll: 1.47 (1.42-1.52)Hoftefraktur: 1.08 (0.98-1.19)Underarm: 1.33 (1.24-1.42)Vertebra frakturer: 2.90 (2.46-3.41)

Ingen forskjeller: - fast vs sporadisk NSAID bruk- diclofenac vs ibuprofen

Use of nonsteroidal anti-inflammatory drugs and risk of fractures.

van Staa TP, Leukens HG, Cooper CBone. 2000 Oct;27(4):563-8.

- Retrospektiv cohort study, UK, 214 577 faste NSAID brukere, 286 850 uregelmessig brukere og 214 577 kontroller- 51 år gj.snitt alder, 62% kvinner, 20% fikk NSAID for ryggsmerter

Resultat:Ikke-vertebrale frakturer, fast NSAID vs kontroll: 1.47 (1.42-1.52)Hoftefraktur: 1.08 (0.98-1.19)Underarm: 1.33 (1.24-1.42)Vertebra frakturer: 2.90 (2.46-3.41)

Ingen forskjeller: - fast vs uregelmessig NSAID bruk- diclofenac vs ibuprofen

Use of oral corticosteroids and risk of fractures.

Van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper CJ Bone Miner Res. 2000 Jun;15(6):993-1000. L

- Retrospektiv cohort study, UK, 244,235 oral corticosteroid brukere og 244,235 kontroller- 57 år gj.snitt alder, 59% kvinner, 40% fikk steroid for luftveis/lunge sykdom

Resultat:Relativ rate frakturer hos steroid brukere vs ikke-steroid brukere:-Ikke-vertebrale frakturer: 1.33 (95% confidence interval [CI], 1.29-1.38), -Hoftefraktur: 1.61 (1.47-1.76)-Underarmsbrudd 1.09 (1.01-1.17)- Vertebra frakturer: 2.60 (2.31-2.92).

Doseavhengig økning I fraktur risk: Hoftefraktur Vertebra fraktur<2.5 mg prednisolon per dag 0.99 (0.82-1.20) 1.55 (1.20-2.01)

2.5-7.5 mg prednisolon per dag 1.77 (1.55-2.02) 2.59 (2.16-3.10)> 7.5 mg prednisolon per dag 2.27 (1.94-2.66) 5.18 (4.25-6.31

All fraktur risiko sank til baseline i løpet av 1-4 år etter seponering av prednisolon

Prophylactic oral ibuprofen or ibuprofen-codeine...

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